Between 1790 and 1845, the Cherokee attempted to become a nation state, lost their ancestral land, endured removal to the Indian Territory, and suffered the destructive Civil War, in which their early alliance with the Confederacy jeopardized their nation. Throughout these tumultuous years, the dominant political figure in the Cherokee Nation was John Ross, whose leadership spanned the entire period. By ancestry, Ross was seven-eighths Scottish, and he grew up in both Cherokee and frontier American environments. He had been educated in English by white men and was a poor speaker of the Cherokee language, but his bi-cultural background allowed him to represent the Cherokee to the Americans in government. He was one of the wealthiest men of the Nation. In terms of heritage, education, status, and economic pursuits, Ross closely resembled his political foes President Andrew Jackson and Governor George R. Gilmer of Georgia. He was among the elite of the Cherokee Nation. By his own person he called into question many of the 19th century European-American assumptions about race and Native American. Ross' life had a pattern similar to those of prominent Anglo-Métis in North America and Canada. Scots and English fur traders in North America were typically men of social status and financial standing who married high-ranking women of Native American ancestry. These alliances helped both the traders and Native Americans. They educated their children in bicultural and multilingual environments. The mixed-race children often married and rose to positions of stature in society, both in political and economic terms. In the changing environment which Cherokees encountered in the 19th century, they needed the skills and language which Ross had developed. The majority of Cherokees ardently supported Ross, electing him as their principal chief in every election from 1828 through 1860. Given his stature and the controversy over Native American affairs in the struggle over territory, there were also a vocal minority of Cherokees and a generation of political leaders in Washington who considered Ross to be dictatorial, greedy, and an "aristocratic leader [who] sought to defraud" the Cherokee Nation. Ross also had influential supporters in Washington, including Thomas L. McKenney, the Commissioner of Indian Affairs (1824 - 1830). He described Ross as the father of the Cherokee Nation, a Moses who "led... his people in their exodus from the land of their nativity to a new country, and from the savage state to that of civilization."

Ross was born in Turkeytown, Alabama, along the Coosa River, near Lookout Mountain, to Mollie McDonald, of mixed-race Cherokee and Scots ancestry, and Daniel Ross, a Scots immigrant trader. Ross' Scots heritage in North America began with William Shorey, a Scottish interpreter who married Ghigooie, a "full-blood" member of the Cherokee Bird clan. In 1769, their daughter Anna Shorey married John McDonald, a Scottish fur trader at Fort Loudoun in Tennessee. The Scottish and English fur traders were men of social standing who arrived with some financial backing. Their children, whether mixed-race or not, in these years shared their status and class. Their daughter Mollie McDonald in 1786 married Daniel Ross, a Scotsman who began to live among the Cherokee as a trader during the American Revolution. Ross spent his childhood with his parents in the area of Lookout Mountain. He saw much of Cherokee society as he encountered the fullblood Cherokee who frequented his father's trading company. As a child, Ross was allowed to participate in Cherokee events such as the Green Corn Festival. Despite Daniel's willingness to allow his son to participate in some Cherokee customs, the elder Ross was determined that John also receive a rigorous classical education. After being educated at home, Ross pursued higher studies with the Reverend Gideon Blackburn, who established two schools in southeast Tennessee for Cherokee children. Classes were in English and students were mostly bicultural like John Ross. Ross finished his education at an academy in South West Point, Tennessee.

At the age of twenty, having completed his education and with bilingual skills, Ross was appointed as US Indian agent to the western Cherokee and sent to Arkansas. He served as an adjutant in a Cherokee regiment during the War of 1812. With them he participated in fighting at the Battle of Horseshoe Bend against the British-allied Creek tribe. Ross then began a series of business ventures. He derived the majority of his wealth from cultivating 170 acres (0.69 km²) in Tennessee worked by twenty slaves. In 1816 he founded Ross's Landing and ferry. In addition, Ross established a trading firm and warehouse. In total, he earned upwards on one-thousand dollars a year. After Ross and the Cherokee were removed to Oklahoma, settlers changed the name of Ross's Landing to Chattanooga. In 1827, Ross moved to Rome, Georgia, to be closer to New Echota, the Cherokee capital, and leading politicians of the nation. In Rome, Ross established a ferry along the headwaters of the Coosa River close to the home of Major Ridge, another wealthy and influential Cherokee leader. He also held 20 slaves who cultivated 170 acres (0.69 km²). By December 1836, Ross's property was appraised at $23,665. He was then one of the five wealthiest men in the Cherokee Nation.

The years 1812 to 1827 were also a period of political apprenticeship for Ross. He had to learn how to conduct negotiations with the United States and the skills required to run a national government. After 1814, Ross's political career, as a Cherokee legislator and diplomat, progressed with the support of individuals such as Principal Chief Pathkiller, Associate Chief Charles R. Hicks, and Major Ridge, an elder statesman of the Cherokee Nation. In 1813, as relations with the United States became more complex, older, uneducated Chiefs like Pathkiller could not effectively defend Cherokee interests. The ascendancy of Ross represented an acknowledgment by the Cherokee that an educated, English-speaking leadership was of national importance. Both Pathkiller and Hicks saw Ross as the future leader of the Cherokee Nation and trained him for this work. Ross served as clerk to Pathkiller and Hicks, where he worked on all financial and political matters of the nation. Equally important in the education of the future leader of the Cherokees was instruction in the traditions of the Cherokee Nation. In a series of letters to Ross, Hicks outlined what was known of Cherokee traditions.

In 1816, the National Council named Ross to his first delegation to Washington. The delegation of 1816 was directed to resolve the sensitive issues of national boundaries, land ownership, and white intrusions on Cherokee land. Of the delegates, only Ross was fluent in English, making him the central figure in the negotiations. This was a unique position for a young man in Cherokee society, which traditionally favored older leaders. Ross's first political position came in November 1817 with the formation of the National Council. He was elected to the thirteen-member body, where each man served two-year terms. The National Council was created to consolidate Cherokee political authority after General Jackson made two treaties with small cliques of Cherokees representing minority factions. Membership in the National Council placed Ross among the ruling elite of the Cherokee leadership. In November 1818, on the eve of the General Council meeting with Cherokee agent Joseph McMinn, Ross was elevated to the presidency of the National Committee. He held this position through 1827. The Council selected Ross because they perceived him to have the diplomatic skill necessary to rebuff US requests to cede Cherokee lands. In this task, Ross did not disappoint the Council. McMinn offered $200,000 US for removal of the Cherokees beyond the Mississippi, which Ross refused.

In 1819, the Council sent Ross to Washington again. He was assuming a larger role among the leadership. The purpose of the delegation was to clarify the provisions of the Treaty of 1817. The delegation had to negotiate the limits of the ceded land and hope to clarify the Cherokee's right to the remaining land. John C. Calhoun, the Secretary of War, pressed Ross to cede large tracts of land in Tennessee and Georgia. Such pressure from the US government would continue and intensify. In October 1822, Calhoun requested that the Cherokee relinquish their land claimed by Georgia, in fulfillment of the United States' obligation under the Compact of 1802. Before responding to Calhoun's proposition, Ross first ascertained the sentiment of the Cherokee people. They were unanimously opposed to cession of land.

In January 1824, Ross traveled to Washington to defend the Cherokees' possession of their land. Calhoun offered two solutions to the Cherokee delegation: either relinquish title to their lands and remove west, or accept denationalization and become citizens of the United States. Rather than accept Calhoun's ultimatum, Ross made a bold departure from previous negotiations. He pressed the Nation's complaints. On April 15, 1824, Ross took the dramatic step of directly petitioning Congress. This fundamentally altered the traditional relationship between an Indian nation and the US government. Never before had an Indian nation petitioned Congress with grievances. In Ross' correspondence, what had previously had the tone of petitions of submissive Indians were replaced by assertive defenders. He was able to argue as well as whites, subtle points about legal responsibilities. This change was apparent to individuals in Washington, including future president John Quincy Adams. He wrote, "[T]here was less Indian oratory, and more of the common style of white discourse, than in the same chief's speech on their first introduction." Adams specifically noted Ross' work as "the writer of the delegation" and remarked that "they [had] sustained a written controversy against the Georgia delegation with greate advantage." The Georgia delegation acknowledged Ross' skill in an editorial in The Georgia Journal, which charged that the Cherokee delegation's letters were fraudulent because they were too refined to have been written or dictated by an Indian.

In January 1827, Pathkiller, the Cherokee's principal chief, and Charles R. Hicks, Ross's mentor, both died. In a letter dated February 23, 1827, to Colonel Hugh Montgomery, the Cherokee Agent, Ross wrote that with the death of Hicks, he had assumed responsibility for all public business of the nation. The year 1827 marked not only the elevation of Ross to principal chief pro tem, but also the climax of political reform of the Cherokee government. The Cherokee Council passed a series of laws creating a bicameral national government. In 1822 they created the Cherokee Supreme Court, capping the creation of a three-branch government. In May 1827, Ross was elected to the twenty-four member constitutional committee, which drafted a constitution calling for a principal chief, a council of the principal chief, and a National Committee, which together would form the General Council of the Cherokee Nation. Although the constitution was ratified in October 1827, it did not take effect until October 1828, at which point Ross was elected principal chief. He was repeatedly reelected and held this position until his death in 1866. The Cherokee had created a system of government with delegated authority capable of dependably formulating a clear, long-range policy to protect national rights. They had a strong leader in Ross who understood the complexities of the United States government and could use that knowledge to implement national policy.

On December 20, 1828, Georgia, fearful that the United States would be unable to effect the removal of the Cherokee Nation, enacted a series of oppressive laws which stripped the Cherokee of their rights and were calculated to force the Cherokee to remove. In this climate, Ross led another delegation to Washington in January 1829 to resolve disputes over non-payment of annuities and the boundary between Georgia and the Cherokee Nation. Rather than lead the delegation into futile negotiations with President Jackson, Ross wrote an immediate memorial to Congress, forgoing the customary correspondence and petitions to the President. Ross found support in Congress from individuals in the National Republican Party, such as Senators Henry Clay, Theodore Frelinghuysen, and Daniel Webster and Representatives Ambrose Spencer and David (Davy) Crockett. Despite this support, in April 1829, John H. Eaton, Secretary of War (1829 - 1831), informed Ross that President Jackson would support the right of Georgia to extend her laws over the Cherokee Nation. In May 1830, Congress endorsed Jackson's policy of removal by passing the Indian Removal Act. It authorized the president to set aside lands west of the Mississippi to exchange for the lands of the Indian nations in the east.

When Ross and the Cherokee delegation failed in their efforts to protect Cherokee lands through dealings with the executive branch and Congress, Ross took the radical step of defending Cherokee rights through the U.S. courts. In June 1830, at the urging of Senator Webster and Senator Frelinghuysen, the Cherokee delegation selected William Wirt, US Attorney General in the Monroe and Adams administrations, to defend Cherokee rights before the U.S. Supreme Court. Wirt argued two cases on behalf of the Cherokee: Cherokee Nation v. Georgia and Worcester v. Georgia. In his decision, Chief Justice John Marshall never acknowledged that the Cherokee were a sovereign nation. He did not compel President Jackson to take action that would defend the Cherokee from Georgia's laws. The Cherokee Nation claim was denied on the grounds that the Cherokees were a "domestic dependent sovereignty" and as such did not have the right as a nation state to sue Georgia. The court later expanded on this position in Worcester v. Georgia, ruling that Georgia could not extend its laws into Cherokee lands. It was not because they were fully sovereign, however, but because they were a domestic dependent sovereignty. As such the court ruled the Cherokee were dependent not on the state of Georgia, but on the United States. According to the series of rulings, Georgia could not extend its laws because that was a power in essence reserved to the federal government. The Cherokee were considered sovereign enough to legally resist the government of Georgia, and were encouraged to do so.

The court carefully maintained that the Cherokee were ultimately dependent on the federal government and were not a true nation state, nor fully sovereign. Thus the dispute was made moot when federal legislation in the form of the Indian Removal Act exercised the federal government's legal power to handle the whole affair. The series of decisions embarrassed Jackson politically, as Whigs attempted to use the issue in the 1832 election. They largely supported his earlier opinion that the "Indian Question" was one that was best handled by the federal government, and not local authorities. In an unusual meeting in May 1832, Supreme Court Justice John McLean spoke with the Cherokee delegation to offer his views on their situation. McLean's advice was to "remove and become a Territory with a patent in fee simple to the nation for all its lands, and a delegate in Congress, but reserving to itself the entire right of legislation and selection of all officers."

McLean's advice precipitated a split within the Cherokee leadership as John Ridge and Elias Boudinot began to doubt Ross' leadership. In February 1833, Ridge wrote Ross advocating that the delegation dispatched to Washington that month should begin removal negotiations with Jackson. However, Ridge and Ross did not have irreconcilable worldviews; neither believed that the Cherokee could fend off Georgian usurpation of Cherokee land. Although Ridge and Ross agreed on this point, they clashed about how best to serve the Cherokee Nation. In this environment, Ross led a delegation to Washington in March 1834 to try to negotiate alternatives to removal. Ross made several proposals; however, the Cherokee Nation may not have approved any of Ross' plans, nor was there reasonable expectation that Jackson would settle for any agreement short of removal. These offers, coupled with the lengthy cross-continental trip, indicated that Ross' strategy was to prolong negotiations on removal indefinitely. He hoped to wear down Jackson's opposition to a treaty that did not require Cherokee removal. Ross' strategy was flawed because it was susceptible to the United States' making a treaty with a minority faction. On May 29, 1834, Ross received word from John H. Eaton, that a new delegation, including Major Ridge, John Ridge, Elias Boudinot, and Ross' younger brother Andrew, collectively called the Ridge Party, had arrived in Washington with the goal of signing a treaty of removal. The two sides attempted reconciliation, but by October 1834 still had not come to an agreement. In January 1835 the factions were again in Washington. Pressured by the presence of the Ridge Party, Ross agreed on February 25, 1835, to exchange all Cherokee lands east of the Mississippi for land west of the Mississippi and 20 million dollars. He made it contingent on the General Council's accepting the terms.

Lewis Cass, Secretary of War, believing that this was yet another ploy to delay action on removal for an additional year, threatened to sign the treaty with John Ridge. On December 29, 1835, the Ridge Party signed the removal treaty with the U.S., although this action was against the will of the majority of Cherokees. Ross unsuccessfully lobbied against enforcement of the treaty. Those Cherokees who did not emigrate to the Indian Territory by 1838 were forced to do so by General Winfield Scott. This forced removal came to be known as the "Trail of Tears". Accepting defeat, Ross convinced General Scott to allow him to supervise much of the removal process. On the Trail of Tears, Ross lost his wife Quatie, a full-blooded Cherokee woman of whom little is known. She died shortly before reaching Little Rock on the Arkansas River. Ross later married again, to Mary Brian Stapler. In the Indian Territory, Ross helped draft a constitution for the entire Cherokee nation in 1839, and was chosen as chief of the nation.

The American Civil War was a test for Ross to hold the nation together, preserve national rights acquired by treaties, and ensure national welfare. As the southern states seceded and formed the Confederacy, slave-owning Cherokee, who formed the core of the old Treaty Party, banded together under the leadership of Stand Watie and pushed for a treaty with the new Confederate government. The Cherokees' own severe internal dissension from the 1820 to the 1840s over issues of acculturation and removal motivated Ross' overriding concern for unity in 1861. Furthermore, Ross understood that "the relations which the Cherokee people sustain toward their white brethren have been established by subsisting treaties with the United States..." The Cherokee right to land, self-government, and annuities from the sale of ancestral lands were all secured in treaties with the United States; Ross knew they would be lost if the Cherokee Nation joined the Confederacy. Seeing the conflict between treaties with the Union and some members' sympathies with the Confederacy, Ross opted for a policy of neutrality to unify the nation and ensure that Cherokee rights were not lost. In February 1861, Ross began a vigorous campaign among the leaders of the Chickasaw, Choctaw, and Creek Nations to advance his policy, emphasizing loyalty to the United States to protect their treaty rights. The policy of neutrality was a skillful attempt to spare the Cherokee the depredations of war and the potential loss of their precious rights, but by July 1861, Ross had been informed that "difficulties of a serious character existed...between half and full blood Cherokees..." Ross attempted to salvage the situation by convening the Executive Council on August 21, 1861, "for the purpose of devising means by which the people may become deeply impressed with the importance of being united in sentiment & action for the welfare of our Common Country." Ross explained how the Cherokee' treaty relationship with the United States dictated the policy of neutrality. Nonetheless, he concluded with, "in my opinion, the time has now arrived when you should signify your consent for the authorization of the nation to adopt preliminary steps for an alliance with the Confederate States..." His shift was understandable in terms of traditional Cherokee political ethos. Any Cherokee leader would have been expected to calmly state and restate the same opinion until a consensus emerged, at which point all Cherokee would either accept the emerging sentiment or withdraw. Ross perceived the forces pushing for ties with the Confederacy to be in the majority; in traditional Cherokee style, he acceded to the majority sentiment in order to preserve unity and harmony.

Despite his attempt to keep the Cherokee united, not all agreed with this position. Before the end of 1861, the Civil War had come to the Indian Territory; the failure of Ross to shield the five nations was complete. The Cherokees had chosen the wrong ally to defend the nation's rights, for the South could not protect the Cherokee Nation. The Union Army invaded it in July 1862. With this defeat, the Cherokee nation was abandoned by the Confederacy. Fearing the loss of the rights for which they had sacrificed their ancestral lands, Ross led a large part of the population back to allegiance to the Union cause. A regiment of Cherokee men enlisted in the Union Army. Ross went to Washington, where the Cherokee leadership hoped he could "advocate our cause, to represent us [in Washington] and exert all your influence to preserve our nationality and our rights." In a letter to President Lincoln before his arrival, Ross outlined a six-point defense of Cherokee rights based on mutual observance of treaty obligations. The skillfully crafted argument absolved Cherokee disloyalty by claiming the treaties were abrogated by the failure of the United States to fulfill the promises it had contracted. Lincoln, a trained lawyer, expressed doubt about the logic of Ross' arguments. Although unwilling to accede to the idea that the United States had special obligations to the Cherokee, Lincoln acknowledged the Cherokees' general right to protection by the government. Ross stayed in Washington from October 1862 through July 1865. In 1863 Stand Watie's troops burned his home of Park Hill in Oklahoma, demonstrating the strong conflicts within the Cherokee nation. Ross continued to defend Cherokee treaty rights and tried to ensure the welfare of the nation for the duration of the war. The government-in-exile received grievances and updates from citizens who remained in the Nation. Ross, who gained access to members of Congress and the Executive, lobbied to aid the Cherokee and other western Indian nations. Although Ross was able to establish and maintain correspondences with Lincoln, Edwin M. Stanton, Secretary of War; and William P. Dole, Commissioner of Indian Affairs, his task remained arduous. His pleas received sympathetic hearing, but he had not convinced the government of its obligations to the Cherokees. Ultimately, Ross was successful in getting Cherokee regiments armed for defense, which allowed the Cherokee to return to the Union. He was never successful in settling the Cherokees' rights with the United States.

In his final annual message on October 1865, Ross assessed the Cherokee experience during the Civil War and his performance as chief. The Cherokee could "have the proud satisfaction of knowing that we honestly strove to preserve the peace within our borders, but when this could not be done,...borne a gallant part in the defense...of the cause which has been crowned with such signal success."

Ross died on August 1, 1866 in Washington, DC.

The City of Chattanooga named the Market Street Bridge in Ross's honor.

The city of Rossville Georgia, just south of the Tennessee state line is named in Ross' honor. The "John Ross House" is located there, and is one of the oldest surviving homes in the Chattanooga area. Ross lived there as a child and received much of his formal education until moving closer to New Echota. Ross sold the home to relatives in 1828.