Frank Cali was born in New York City to Augusto and Agata Cesare, both natives of Palermo, Sicily. His father ran a household goods store in Palermo and a video store in Bensonhurst, Brooklyn. He had a clean police record in the United States, even though he was mentioned in the Pizza Connection investigation, when police discovered that he was a partner of Domenico Adamita, allied to Sicilian Mafia boss Gaetano Badalamenti.
Frank Cali is the nephew-in-law of Sicilian mobster John Gambino, and has close ties to the once powerful Sicilian Mafia family led by Salvatore Inzerillo. Cali is also a great-nephew of Bonanno crime family mobsters Giovanni Bonventre and Vito Bonventre. Cali was also related to Gambino boss Paul Castellano.
As a young man, Cali bonded with Gambino mobster Jackie D'Amico, a lieutenant of Gambino boss John Gotti who operated a crew on 18th Avenue in Brooklyn. In January 1997, the FBI reported to Italian authorities that Cali had been "combined" into the Gambino family. Cali was promoted to acting capo when D'Amico became acting boss. Cali ran several import-export companies in Brooklyn, including Circus Fruits Wholesale in Fort Hamilton, Brooklyn.
Cali also maintained ties with the Sicilian Mafia. He married Rosaria Inzerrilo, a sister of Pietro Inzerillo and a relative of Gambino associate Frank Inzerillo, a member of the Palermitan Inzerillo family. In the early 1980s, after losing the Second Mafia War against the Corleonesi of Totò Riina, the Inzerillo family was forced to flee Sicily. Cali and old Palermo boss Filippo Casamento supported the return of the Inzerillos to Palermo, according to Italian authorities.
According to the Italian Polizia di Stato (State Police), Cali is also a member of the Sicilian Cosa Nostra. He was the contact for Sicilian mafiosi who traveled to New York to meet him, do business, and update him on Sicilian affairs. "He's our friend and he is everything over there", confided Sicilian mobster Gianni Nicchi to his boss Antonio Rotolo, after a trip in 2003. Nicchi is one of the Sicilian 'men of honour' who went back and forth between Palermo and the US for drug trafficking.
In early 2003, Cali and fellow captain Leonard "Lenny" DiMaria began extorting 'mob taxes' from Joseph Vollaro, the owner of a trucking and contracting company that was helping build a NASCAR speedway on Staten Island. Vollero was eventually forced to pay tens of thousands of dollars as tribute to D'Amico and Gambino boss Nicholas Corozzo. In 2004, to avoid prison time for a cocaine conviction, Vollero began working with federal authorities as an informant. Vollero's undercover work led to a massive indictment four years later.
On February 8, 2008, Cali and 61 other New York Cosa Nostra associates were arrested and charged with federal racketeering charges. as part of Operation Old Bridge. Old Bridge terminated the drug trafficking between the Sicilian Mafia and the Gambino family. Prosecutors claimed that Cali acted as the Gambino "ambassador to the Sicilian mobsters" and as a liaison between D'Amico and the Sicilian connections to the Inzerillo family. Cali was charged with racketeering, extortion, and conspiracy along with D'Amico and DiMaria.
On June 4, 2008, Cali pleaded guilty to conspiring to extort money from Vollaro. Cali was incarcerated at the Metropolitan Detention Center in Brooklyn, New York. On April 6, 2009, he was released from prison.
Around 2009, Cali's uncle John Gambino was elevated to the family's ruling panel, according to court papers filed in Brooklyn Federal Court. The U.S. Justice Department demanded that Cali avoid all contact with Gambino, except for weddings or holiday celebrations approved in advance by Cali's probation officer.
In October 2012, Cali was identified by New York crime reporter Jerry Capeci as the new underboss of the Gambino crime family. Capeci has previously identified Domenico Cefalu, a member of the same Sicilian faction as Cali, as the current boss of the group. Though his status remains unclear, the promotion of both men follows a period in which John Gambino was a street boss within the family, showing that the Sicilian group has remained dominant in recent years. In July 2013, it was reported that Cali turned down the position of boss of the family.
In August 2015, Daily News reported Cali had taken over as acting boss of the Gambino family from the aging Domenico Cefalu.