In early 1957, Genovese decided to move on Costello. Genovese ordered Vincent Gigante to murder Genovese family boss Costello, and on May 2, 1957, Gigante shot and wounded Costello outside his apartment building. Although the wound was superficial, it persuaded Costello to relinquish power to Genovese and retire. A doorman identified Gigante as the gunman, however, in 1958, Costello testified that he was unable to recognize his assailant; Gigante was acquitted on charges of attempted murder.
With Costello gone, Genovese and Gambino allegedly ordered Anastasia's murder. Gambino gave the contract to Joe Profaci, who then allegedly gave it to the Gallo crew, headed by Joseph "Crazy Joe" Gallo, with Anastasia being murdered on October 25, 1957, in the barbershop of the Park Sheraton Hotel in Midtown Manhattan. Gambino then became the new boss of the Mangano crime family, which was renamed the Gambino crime family.
In November 1957, immediately after the Anastasia murder, after taking control of the Luciano crime family from Costello, Genovese wanted to legitimize his new power by holding a national Cosa Nostra meeting. Genovese elected Buffalo, New York boss and Commission member, Stefano "The Undertaker" Magaddino, who in turn chose northeastern Pennsylvania crime boss Joseph Barbara and his underboss Russell Bufalino to oversee all the arrangements for the Apalachin meeting. Cuba was one of the Apalachin topics of discussion, particularly the gambling and narcotics smuggling interests of La Cosa Nostra on the island. The international narcotics trade was also an important topic on the Apalachin agenda. The New York garment industry interests and rackets, such as loansharking to the business owners and control of garment center trucking, were other important topics on the Apalachin agenda.
On November 14, 1957, powerful mafiosi from the United States and Italy convened at Barbara's estate in Apalachin, New York. The meeting agenda included the resolution of open questions on illegal gambling and narcotics dealing, particularly in the New York City area. State trooper Edgar D. Croswell had become aware that Barbara's son was reserving rooms in local hotels along with the delivery of a large quantity of meat from a local butcher to the Barbara home. That made Croswell suspicious, and he therefore decided to keep an eye on Barbara's house. When the state police found many luxury cars parked at Barbara's home they began taking down license plate numbers. Having found that many of these cars were registered to known criminals, state police reinforcements came to the scene and began to set up a roadblock. When the mobsters discovered the police presence, they started fleeing the gathering by car and by foot. Many Mafiosi escaped through the woods surrounding the Barbara estate; Gambino is thought to have attended the meeting, but was not one of the mobsters apprehended. The police stopped a car driven by Bufalino, whose passengers included Genovese and three other men, at a roadblock as they left the estate; Bufalino said that he had come to visit his sick friend, Barbara. Genovese said he was just there for a barbecue and to discuss business with Barbara. The police let him go.