Mangano was named head of what was then the Mineo family in 1931, following the Castellammarese War. He was one of the original bosses of the modern Five Families, the others being Salvatore Maranzano, Lucky Luciano, Joe Profaci and Tommy Gagliano.

Mangano was an older mafioso who was very much steeped in the Old World ideals of "honor," "tradition," "respect" and "dignity." While he was still in many ways a Mustache Pete, he was more forward looking than Maranzano and Joe Masseria, and was thus allowed to stay in power after Luciano and the other "Young Turks" eliminated Maranzano.

Mangano and Camarda established the City Democratic Club, which promoted bedrock American values in the front room, while illegal activities were planned in the backroom. It became a regular meeting place for the members of Murder, Inc., the infamous gang of assassins who, for a price, did the bidding of syndicate mobsters. Vincent's underboss, Albert "Mad Hatter" Anastasia, was also operating head of Murder, Inc. and was a frequent patron of the club, as was Phillip Mangano.

Mangano made the waterfront his family's main income producer. He and his associates would threaten to prevent cargo from being loaded or unloaded if the shipping company refused to pay a tribute. This effort was helped by the family's control of Brooklyn Local 1814 of the International Longshoremen's Association; its president, Anthony Anastasio (Albert's brother; he kept the original spelling of his last name) was a member of the family. Mangano would force workers to pay a fee for every day they worked on the docks - because of this, the mob knew exactly what was on each ship and could choose what to steal.

Other prominent members during Mangano's time were Carlo Gambino, Aniello "Neil" Dellacroce and Paul Castellano.

Mangano was the only one of the bosses who retained the old ways so resentment grew from a new breed of mob leaders, including Anastasia. Anastasia grew to prefer the company of other mob bosses such as Charlie "Lucky" Luciano, Frank Costello and Louis "Lepke" Buchalter. Likewise, Mangano grew to resent and mistrust Anastasia. The two men regularly argued and fought, having to be pulled apart - possibly for the protection of the elder Mangano who was no physical match for his younger underboss.

Although it ultimately took a full 20 years of working together for matters to come to a head, Mangano eventually met his end at the hands of Anastasia, or so it is believed.

In 1951, Anastasia is believed to have heard of a plot to kill him being formed by his boss, and decided to take pre-emptive action in what he ultimately described as "self defense." Philip Mangano was found murdered near Sheepshead Bay, Brooklyn, on April 19, 1951. Vincent also vanished the same day without trace. His body has never been found. Though Anastasia never admitted to having a hand in the Mangano murders, he managed to convince the heads of the other families that Vincent Mangano had been plotting to have him killed (a claim backed up by Frank Costello), and he was named as the new boss of the family.