The first attempt to explore western South America was undertaken in 1522 by Pascual de Andagoya. The native South Americans he encountered told him about a gold rich territory called Virú, which was on a river called Pirú (later corrupted to Perú) and from which they came. These reports were related by the Spanish - Inca mestizo writer Garcilaso de la Vega in his famous Comentarios Reales de los Incas (1609).

Andagoya eventually established contact with several Native American curacas (chiefs), some of whom he later claimed were sorcerers and witches. Having reached as far as the San Juan River (part of the present boundary between Ecuador and Colombia), Andagoya fell very ill and decided to return. Back in Panama, he spread the news and stories about "Pirú" – a great land to the south rich with gold (the legendary El Dorado). These revelations, along with the accounts of success of Hernán Cortés in Mexico years before, caught the immediate attention of Pizarro, prompting a new series of expeditions to the south in search of the riches of the Incan Empire.

In 1524, while still in Panama, Pizarro formed a partnership with a priest, Hernando de Luque, and a soldier, Diego de Almagro, to explore and conquer the South. Pizarro, Almagro, and Luque later renewed their compact more explicitly, agreeing to conquer and divide equally among themselves the opulent empire they hoped to discover. While historians agree their accord was strictly oral (no written document exists to prove otherwise), they are known to have dubbed their enterprise the "Empresa del Levante" and determined that Pizarro would command the expedition, Almagro would provide the military and food supplies, and Luque would be in charge of finances and any additional provisions they might need.

On 13 September 1524, the first of three expeditions left from Panama for the conquest of Peru with about 80 men and 40 horses. Diego de Almagro was left behind because he was to recruit men, gather additional supplies, and join Pizarro later. The Governor of Panama, Pedro Arias Dávila, at first approved in principle of exploring South America. Pizarro's first expedition, however, turned out to be a failure as his conquistadors, sailing down the Pacific coast, reached no farther than Colombia before succumbing to such hardships as bad weather, lack of food, and skirmishes with hostile natives, one of which caused Almagro to lose an eye by arrow shot. Moreover, the place names the Spanish bestowed along their route, including Puerto deseado (desired port), Puerto del hambre (port of hunger), and Puerto quemado (burned port), only confirm their straits. Fearing subsequent hostile encounters like the one the expedition endured at the Battle of Punta Quemada, Pizarro chose to end his tentative first expedition and return to Panama.

Two years after the first very unsuccessful expedition, Pizarro, Almagro, and Luque started the arrangements for a second expedition with permission from Pedrarias Dávila. The Governor, who himself was preparing an expedition north to Nicaragua, was reluctant to permit another expedition, having lost confidence in the outcome of Pizarro's expeditions. The three associates, however, eventually won his trust and he acquiesced. Also by this time, a new governor was to arrive and succeed Pedrarias Dávila. This was Pedro de los Ríos, who took charge of the post in July 1526 and had manifested his initial approval of Pizarro's expeditions (he would later join him several years later in Peru).

In August 1526, after all preparations were ready, Pizarro left Panama with two ships with 160 men and several horses, reaching as far as the Colombian San Juan River. Soon after arriving the party separated, with Pizarro staying to explore the new and often perilous territory off the swampy Colombian coasts, while the expedition's second - in - command, Almagro, was sent back to Panama for reinforcements. Pizarro's Piloto Mayor (main pilot), Bartolomé Ruiz, continued sailing south and, after crossing the equator, found and captured a balsa (raft) of natives from Tumbes who were supervising the area. To everyone's surprise, these carried a load of textiles, ceramic objects, and some much desired pieces of gold, silver, and emeralds, making Ruiz's findings the central focus of this second expedition which only served to pique the conquistadors' interests for more gold and land. Some of the natives were also taken aboard Ruiz's ship to serve later as interpreters.

He then set sail north for the San Juan river, arriving to find Pizarro and his men exhausted from the serious difficulties they had faced exploring the new territory. Soon Almagro also sailed into the port with his vessel laden with supplies, and a considerable reinforcement of at least eighty recruited men who had arrived at Panama from Spain with the same expeditionary spirit. The findings and excellent news from Ruiz along with Almagro's new reinforcements cheered Pizarro and his tired followers. They then decided to sail back to the territory already explored by Ruiz and, after a difficult voyage due to strong winds and currents, reached Atacames in the Ecuadorian coast. Here they found a very large native population recently brought under Inca rule. Unfortunately for the conquistadors, the warlike spirit of the people they had just encountered seemed so defiant and dangerous in numbers that the Spanish decided not to enter the land.

After much wrangling between Pizarro and Almagro, it was decided that Pizarro would stay at a safer place, the Isla de Gallo, near the coast, while Almagro would return yet again to Panama with Luque for more reinforcements – this time with proof of the gold they had just found and the news of the discovery of an obvious wealthy land they had just explored. The new governor of Panama, Pedro de los Ríos, had learned of the mishaps of Pizarro's expeditions and the deaths of various settlers who had gone with him. Fearing an unsuccessful outcome, he outright rejected Almagro's application for a third expedition in 1527.

In addition, he ordered two ships commanded by Juan Tafur to be sent immediately with the intention of bringing Pizarro and everyone back to Panama. The leader of the expedition had no intention of returning, and when Tafur arrived at the now famous Isla de Gallo, Pizarro drew a line in the sand, saying: "There lies Peru with its riches; Here, Panama and its poverty. Choose, each man, what best becomes a brave Castilian."

Only thirteen men decided to stay with Pizarro and later became known as "The Famous Thirteen" (Los trece de la fama), while the rest of the expeditioners left back with Tafur aboard his ships. Ruiz also left in one of the ships with the intention of joining Almagro and Luque in their efforts to gather more reinforcements and eventually return to aid Pizarro. Soon after the ships left, the 13 men and Pizarro constructed a crude boat and left nine miles (14 km) north for La Isla Gorgona, where they would remain for seven months before the arrival of new provisions.

Back in Panama, Pedro de los Ríos (after much convincing by Luque) had finally acquiesced to the requests for another ship, but only to bring Pizarro back within six months and completely abandon the expedition. Both Almagro and Luque quickly grasped the opportunity and left Panama (this time without new recruits) for La Isla Gorgona to once again join Pizarro. On meeting with Pizarro, the associates decided to continue sailing south on the recommendations of Ruiz's Indian interpreters. By April 1528, they finally reached the northwestern Peruvian Tumbes Region. Tumbes became the territory of the first fruits of success the Spanish had so long desired, as they were received with a warm welcome of hospitality and provisions from theTumpis, the local inhabitants. On subsequent days two of Pizarro's men reconnoitered the territory and both, on separate accounts, reported back the incredible riches of the land, including the decorations of silver and gold around the chief's residence and the hospitable attentions which they were received with by everyone. The Spanish also saw, for the first time, the Peruvian Llama which Pizarro called the "little camels". The natives also began calling the Spanish the "Children of the Sun" due to their fair complexion and brilliant armor. Pizarro, meanwhile, continued receiving the same accounts of a powerful monarch who ruled over the land they were exploring. These events only served as evidence to convince the expedition of the wealth and power displayed at Tumbes as an example of the riches the Peruvian territory had awaiting to conquer. The conquistadors decided to return to Panama to prepare the final expedition of conquest with more recruits and provisions. Before leaving, however, Pizarro and his followers sailed south not so far along the coast to see if anything of interest could be found. Historian William H. Prescott recounts that after passing through territories they named such as Cabo Blanco, port of Payta, Sechura, Punta de Aguja, Santa Cruz, and Trujillo (founded by Almagro years later), they finally reached for the first time the ninth degree of the southern latitude in South America. On their return towards Panama, Pizarro briefly stopped at Tumbes, where two of his men had decided to stay to learn the customs and language of the natives. Pizarro was also offered a native or two himself, one of which was later baptized as Felipillo and served as an important interpreter, the equivalent of Cortés' La Malinche of Mexico. Their final stop was at La Isla Gorgona, where two of his ill men (one had died) had stayed before. After at least eighteen months away, Pizarro and his followers anchored off the coasts of Panama to prepare for the final expedition.

When the new governor of Panama, Pedro de los Ríos, had refused to allow for a third expedition to the south, the associates resolved for Pizarro to leave for Spain and appeal to the sovereign in person. Pizarro sailed from Panama for Spain in the spring of 1528, reaching Seville in early summer. King Charles I, who was at Toledo, had an interview with Pizarro and heard of his expeditions in South America, a territory the conquistador described as very rich in gold and silver which he and his followers had bravely explored "to extend the empire of Castile." The King, who was soon to leave for Italy, was impressed at the accounts of Pizarro and promised to give his support for the conquest of Peru. It would be Queen Isabel, however, who, in the absence of the King, would sign the Capitulación de Toledo, a license document which authorized Francisco Pizarro to proceed with the conquest of Peru. Pizarro was officially named the Governor, Captain General, and the "Adelantado" of the New Castile for the distance of 200 leagues along the newly discovered coast, and invested with all the authority and prerogatives, his associates being left in wholly secondary positions (a fact which later incensed Almagro and would lead to eventual discords with Pizarro). One of the conditions of the grant was that within six months Pizarro should raise a sufficiently equipped force of two hundred and fifty men, of whom one hundred might be drawn from the colonies.

This gave Pizarro time to leave for his native Trujillo and convince his brother Hernando Pizarro and other close friends to join him on his third expedition. Along with him also came Francisco de Orellana, who would later discover and explore the entire length of the Amazon River. Two more of his brothers, Juan Pizarro and Gonzalo Pizarro, would later decide to also join him as well as his cousin Pedro Pizarro who served as his page. When the expedition was ready and left the following year, it numbered three ships, one hundred and eighty men, and twenty - seven horses.

Since Pizarro could not meet the number of men the Capitulación had required, he sailed clandestinely from the port of Sanlúcar de Barrameda for the Canary Island of La Gomera in January 1530. He was there to be joined by his brother Hernando and the remaining men in two vessels that would sail back to Panama. Pizarro's third and final expedition left Panama for Peru on 27 December 1530.

In 1532 Pizarro once again landed in the coasts near Ecuador, where some gold, silver, and emeralds were procured and then dispatched to Almagro, who had stayed in Panama to gather more recruits. Though Pizarro's main objective was then to set sail and dock at Tumbes like his previous expedition, he was forced to confront the Punian natives in the Battle of Puná, leaving three Spaniards dead and 400 dead or wounded Punians. Soon after, Hernando de Soto, another conquistador that had joined the expedition, arrived to aid Pizarro and with him sailed towards Tumbes, only to find the place deserted and destroyed. Their two fellow conquistadors expected they had disappeared or died under murky circumstances. The chiefs explained the fierce tribes of Punians had attacked them and ransacked the place.

As Tumbes no longer afforded the safe accommodations Pizarro sought, he decided to lead an excursion into the interior of the land and established the first Spanish settlement in Peru (third in South America after Santa Marta, Colombia, in 1526), calling it San Miguel de Piura in July 1532. The first repartimiento in Peru was established here. After these events, Hernando de Soto was dispatched to explore the new lands and, after various days away, returned with an envoy from the Inca himself and a few presents with an invitation for a meeting with the Spaniards.

Following the defeat of his brother, Huáscar, Atahualpa had been resting in the Sierra of northern Peru, near Cajamarca, in the nearby thermal baths known today as the Baños del Inca (Incan Baths). After marching for almost two months towards Cajamarca, Pizarro and his force of just 106 foot soldiers and 62 horsemen arrived and initiated proceedings for a meeting with Atahualpa. Pizarro sent Hernando de Soto, friar Vicente de Valverde and native interpreter Felipillo to approach Atahualpa at Cajamarca's central plaza. Atahualpa, however, refused the Spanish presence in his land by saying he would "be no man's tributary." His complacency, because there were fewer than 200 Spanish as opposed to his 80,000 soldiers sealed his fate and that of the Incan empire.

Atahualpa's refusal led Pizarro and his force to attack the Incan army in what became the Battle of Cajamarca on 16 November 1532. The Spanish were successful and Pizarro executed Atahualpa's 12 man honor guard and took the Inca captive at the so-called ransom room. Despite fulfilling his promise of filling one room (22 feet (7 m) by 17 feet (5 m)) with gold and two with silver, Atahualpa was convicted of killing his brother and plotting against Pizarro and his forces, and was executed by garrote on 26 July 1533. Pizarro wished to find a reason for executing Atahualpa without angering the people he was attempting to subdue. Pizarro's brother Hernando and de Soto opposed Atahualpa's execution, considering it an injustice. They objected to the evidence as wholly insufficient and were of the opinion that Pizzaro had no competence to sentence a sovereign prince in his own dominions.

A year later, Pizarro invaded Cuzco with indigenous troops and with it sealed the conquest of Peru. It is argued by some historians that the growing resistance from the new Inca, Manco Inca Yupanqui, prolonged the conquest. Manco Inca Yupanqui was the brother of the puppet ruler, Túpac Huallpa.

During the exploration of Cuzco, Pizarro was impressed and through his officers wrote back to King Charles I of Spain, saying:

"This city is the greatest and the finest ever seen in this country or anywhere in the Indies... We can assure your Majesty that it is so beautiful and has such fine buildings that it would be remarkable even in Spain."

After the Spanish had sealed the conquest of Peru by taking Cuzco in 1533, Jauja in the fertile Mantaro Valley was established as Peru's provisional capital in April 1534. But it was too far up in the mountains and far from the sea to serve as the Spanish capital of Peru. Pizarro thus founded the city of Lima in Peru's central coast on 18 January 1535, a foundation that he considered as one of the most important things he had created in life.

After the final effort of the Inca to recover Cuzco had been defeated by Almagro, a dispute occurred between him and Pizarro respecting the limits of their jurisdiction. This led to confrontations between the Pizarro brothers and Almagro, who was eventually defeated during the Battle of Las Salinas (1538) and executed. Almagro's son, also named Diego and known as "El Mozo", was later stripped of his lands and left bankrupt by Pizarro.

Atahualpa's wife, ten year old Cuxirimay Ocllo Yupanqui, was with Atahualpa's army in Cajamarca and had stayed with him while he was imprisoned. Following his execution she was taken to Cuzco and given the name Dona Angelina. By 1538 it was known she was Pizarro's mistress, having borne him two sons, Juan and Francisco.

In Lima, Peru on 26 June 1541 "a group of twenty heavily armed supporters of Diego Almagro II stormed Pizarro's palace, assassinated him, and then forced the terrified city council to appoint young Almagro as the new governor of Peru", according to Burkholder and Johnson. "Most of Pizarro's guests fled, but a few fought the intruders, numbered variously between seven and 25. While Pizarro struggled to buckle on his breastplate, his defenders, including his half brother Alcántara, were killed. For his part Pizarro killed two attackers and ran through a third. While trying to pull out his sword, he was stabbed in the throat, then fell to the floor where he was stabbed many times." Pizarro (who now was maybe as old as 70 years, and at least 62), collapsed on the floor, alone, painted a cross in his own blood and cried for Jesus Christ. He reportedly cried: Come my faithful sword, companion of all my deeds. He died moments after. Diego de Almagro the younger was caught and executed the following year after losing the battle of Chupas.

Pizarro's remains were briefly interred in the cathedral courtyard; at some later time his head and body were separated and buried in separate boxes underneath the floor of the cathedral. In 1892, in preparation for the anniversary of Columbus' discovery of the Americas, a body believed to be that of Pizarro was exhumed and put on display in a glass coffin. However, in 1977 men working on the cathedral's foundation discovered a lead box in a sealed niche, which bore the inscription "Here is the head of Don Francisco Pizarro Demarkes, Don Francisco Pizarro who discovered Peru and presented it to the crown of Castile." A team of forensic scientists from the United States, led by Dr. William Maples, was invited to examine the two bodies, and they soon determined that the body which had been honored in the glass case for nearly a century had been incorrectly identified. The skull within the lead box not only bore the marks of multiple sword blows, but the features bore a remarkable resemblance to portraits made of the man in life.

By his marriage to N de Trujillo, Pizarro had a son also named Francisco, who married his relative Inés Pizarro, without issue. After Pizarro's death, Inés Yupanqui, whom he took as a mistress, favourite sister of Atahualpa, who had been given to Francisco in marriage by her brother, married a Spanish cavalier named Ampuero and left for Spain, taking her daughter who would later be legitimized by imperial decree. Francisca Pizarro Yupanqui eventually married her uncle Hernando Pizarro in Spain, on 10 October 1537; a third son of Pizarro who was never legitimized, Francisco, by Dona Angelina, a wife of Atahualpa that he had taken as a mistress, died shortly after reaching Spain.

Historians have often compared Pizarro and Cortés' conquests in North and South America as very similar in style and career. Pizarro, however, faced the Incas with a smaller army and fewer resources than Cortés at a much greater distance from the Spanish Caribbean outposts that could easily support him, which has led some to rank Pizarro slightly ahead of Cortés in their battles for conquest. Based on sheer numbers alone, Pizarro's military victory was one of the most improbable in recorded history. For example, Pizarro had fewer soldiers than George Armstrong Custer did at the Battle of the Little Big Horn, while the Incas commanded forty times as many soldiers as Crazy Horse and Sitting Bull did.

Though Pizarro is well known in Peru for being the leader behind the Spanish conquest of the Inca Empire, a growing number of Peruvians regard him as a kind of criminal. By taking advantage of the natives, Pizarro ruled Peru for almost a decade and initiated the decline of Inca culture. The Incas’ polytheistic religion was replaced by Christianity and both Quechua and Aymara — the main Inca languages — were reduced to a marginal role in society for centuries, while Spanish became the official language of Peru, Ecuador, Bolivia and Chile. The cities of the Inca Empire were transformed into Spanish, Catholic cities. Pizarro is also vilified for having ordered Atahualpa's death despite his paid ransom of filling a room with gold and two with silver which was later split among all his closest Spanish associates after a fifth share had been set aside for the king.

In the early 1930s, sculptor Ramsey MacDonald created three copies of an anonymous European foot soldier resembling a conquistador with a helmet, wielding a sword and riding a horse. The first copy was offered to Mexico to represent Hernán Cortés, though it was rejected. Since the Spanish conquerors had the same appearance with helmet and beard, the statue was taken to Lima in 1934. One other copy of the statue resides in Wisconsin. The mounted statue of Pizarro in the Plaza Major in Trujillo, Spain, was created by Charles Rumsey, an American sculptor. It was presented to the city by his widow in 1926.

In 2003, after years of lobbying by indigenous and mixed raced majority requesting for the equestrian statue of Pizarro to be removed, the mayor of Lima, Luis Castañeda Lossio, approved the transfer of the statue to another location: an adjacent square to the country's Government Palace. Since 2004, however, Pizarro's statue has been placed in a rehabilitated park surrounded by the recently restored 17th century pre-Hispanic murals in the Rímac District. The statue faces the Rímac River and the Government Palace.

After their return from Peru and notoriously rich, the Pizarro family erected a plateresque - style palace on the corner of the Plaza Mayor in Trujillo, Spain. It was said to have been constructed on the orders of Pizarro's daughter, Francisca Pizarro Yupanqui. It became an instant recognizable symbol of the plaza. The opulent palace is sctructured in four stands, giving it the significance of the coat of arms of the Pizarro family, which is situated at one of its corner balconies displaying its iconographic content. At one of its sides it displays Francisco Pizarro and, at the other, his wife, the Inca princess Inés Huaylas, along with their daughter Francisca Pizarro Yupanqui and her husband Hernando Pizarro. The building's decor includes plateresque ornaments and balustrades.