In 1926 Giancana was arrested for murder. However, charges were dropped after the key witness was murdered. He was later sent to prison for theft and burglary. On his release he went to work for leading gangster Paul Ricca. By the 1950s Giancana was one of the leading crime bosses in Chicago.
In 1960 Giancana was involved in talks with Allen W. Dulles, the director of the Central Intelligence Agency (CIA), about the possibility of murdering Fidel Castro. It is claimed that during the 1960 presidential election Giancana used his influence in Illinois to help John F. Kennedy defeat Richard Nixon. The two men, at that time, shared the same girlfriend, Judith Campbell Exner.
After becoming president John F. Kennedy appointed his brother, Robert Kennedy, as U.S. Attorney General. The two men worked closely together on a wide variety of issues including the attempt to tackle organized crime. One of their prime targets was to get Giancana arrested.
On 22nd November, 1963, President Kennedy was assassinated. Rumours began to circulate that Giancana and other gang bosses such as Santos Trafficante, Carlos Marcello, and Johnny Roselli, were involved in the crime.
In 1975 Frank Church and his Select Committee to Study Governmental Operations with Respect to Intelligence Activities discovered that Judith Campbell had been involved with both Giancana and John F. Kennedy. It emerged that during the 1960 presidential election Campbell took messages from Giancana to Kennedy. Campbell later claimed these messages concerned the plans to murder Fidel Castro. Kennedy also began an affair with Campbell and used her as a courier to carry sealed envelopes to Giancana. He told her they contained "intelligence material" concerning the plot to kill Castro.
Giancana was now ordered to appear before Church's committee. However, before he could appear, on 19th June, 1975, Sam Giancana was murdered in his own home. He had a massive wound in the back of the head. He had also been shot six times in a circle around the mouth.
On 14th January, 1992, the New York Post claimed that Hoffa, Santos Trafficante and Carlos Marcello had all been involved in the assassination of President John F. Kennedy. Frank Ragano was quoted as saying that at the beginning of 1963 Hoffa had told him to take a message to Trafficante and Marcello concerning a plan to kill Kennedy. When the meeting took place at the Royal Orleans Hotel, Ragano told the men: "You won't believe what Hoffa wants me to tell you. Jimmy wants you to kill the president." He reported that both men gave the impression that they intended to carry out this order.
In 1992 Giancana's nephew published Double Cross: The Story of the Man Who Controlled America. The book attempted to establish that Giancana had rigged the 1960 Presidential election vote in Cook County on John Kennedy's behalf, which effectively gave Kennedy the election. It is argued that Kennedy reneged on the deal and therefore Giancana had him killed.
In his autobiography, Mob Lawyer (1994) (co-written with journalist Selwyn Raab) Frank Ragano added that in July, 1963, he was once again sent to New Orleans by Hoffa to meet Santos Trafficante and Carlos Marcello concerning plans to kill President John F. Kennedy. When Kennedy was killed Hoffa apparently said to Ragano: "I told you could do it. I'll never forget what Carlos and Santos did for me." He added: "This means Bobby is out as Attorney General". Marcello later told Ragano: "When you see Jimmy (Hoffa), you tell him he owes me and he owes me big."