Giancana’s various ties to JFK have long been the subject of speculation. The mobster helped raise money for JFK’s crucial West Virginia primary campaign, or had he arranged to pay off appropriate political figures? Many historians believe that ballot stuffing in Chicago helped ensure Kennedy’s election in 1960. It has been claimed that Joseph Kennedy had done a deal with Giancana to guarantee that he would arrange to rig the presidential election in Illinois, a critical state for campaigning candidates, and ensure that his son John would become president. Giancana himself reportedly claimed that he had helped run a vote-stealing scam in Cook County, Illinois, a district that had been the deciding factor in Kennedy’s victory. Paul D'Amato, a mutual friend of Sinatra's and Giancana's, had used his influence with sheriffs who gambled illegally in Greenbriar County to encourage the coal miners' unions, and anyone else with whom they had influence in the West Virginia area, to vote for the Kennedy ticket. It was a favour Sam Giancana would not let Sinatra, or the Kennedys, forget.

The Mob had agreed to help the Kennedys, but obviously expected something in return. They did not count on the new president and his brother returning the favour by going after them with a vengeance, by investigating the men that had helped JFK become president in his attempt to stamp out organized crime in America.

The relationship between Giancana and the Kennedys became complicated when it was revealed that Giancana’s girlfriend, Judith Exner, was also having an affair with John Kennedy when he was in office. Judith Exner admitted to Larry King on television in 1992 that she repeatedly acted as a courier, shipping satchels of money between the Chicago boss and John Kennedy, used to help Kennedy, the underdog, defeat Hubert Humphrey who was the favourite in the election, adding further proof to voter fraud. She even telephoned JFK at least seventy times after he had been inaugurated at the White House, a fact discovered by FBI chief, J. Edgar Hoover. On March 27, 1962, Hoover apparently persuaded the President to discontinue his relationship with Exner, or at least make sure the telephone connection was broken off.

In late 1960, John F. Kennedy picked as attorney general, his 35-year-old brother Robert. Sam Giancana later said that as far as he was concerned, this was a sucker punch he had not expected. Sam had certain favours he had planned to ask of the Kennedys in the near future, and he expected his wishes to be granted because of his involvement in the successful West Virginia primary.

In March 1961, Giancana visited Sinatra at the Fontainebleau in Miami. He wanted Robert Kennedy to back off from his investigation of Sam's friends, and he wanted Frank Sinatra to talk to Bobby's father, Joseph Kennedy, about the possibility of Bobby agreeing to do just that. According to a wiretapped phone conversation between Giancana and Johnny Roselli . . . Frank had said to Sam, while they were in Florida, "Don't worry about it. If I can't talk to the old man (Joseph Kennedy), I'm gonna talk to the man (Jack Kennedy)."

Sinatra was pushing for Peter Lawford to talk to Bobby Kennedy about laying off Giancana. "Lawford did talk to Bobby and was told to mind his own business. Bobby was going after Sam with a vengeance."

Whatever Giancana’s specific link to JFK was, the two men had a nemesis in common: Fidel Castro, whom Mob leaders hated because he had taken over Cuba, with its extensive gambling rackets. The Kennedy Administration, obviously, viewed Castro’s Communist regime as a threat to national security, as evidenced by the infamous Bay of Pigs invasion in April 1961. The tie between Giancana and Kennedy would again be the subject of speculation when information later surfaced that the Mafia and the Central Intelligence Agency (CIA) had joined forces sometime in the 1960s to plot Castro’s assassination. It is believed that Judy Exner was again messenger between JFK and Giancana as they plotted to assassinate Castro.

The CIA wanted to oust Fidel Castro from power and judged that the best way to do so would be to secure help from the mob, who had experience in assassinations. The deal was that if the Mafia helped with this matter, they would be allowed to control the criminal elements under the new regime. Because Giancana lost a lot of money following Castro's nationalizing policy, he was hungry for some payback. President Kennedy approved the operation. But problems arose for Momo. First of all, the CIA decided that Castro was unreachable and that an invasion of the island by Cuban expatriates was a better option. When the Bay of Pigs assault ended in disaster, JFK decided the political implications were too severe and let the matter go. The second problem was Bobby Kennedy, now Attorney General, and his rejuvenated desire to crush organized crime. As a result, the FBI began tailing Giancana's every move. Both Momo and the CIA seethed at their President's actions. The Mafia kingpin thought about releasing his incriminating material on the Kennedy brothers but the CIA officers advised against it as the documents had been obtained illegally. Marilyn Monroe was involved with both brothers and had confessed her love for Bobby - and Giancana saw this as an opportunity to strike.

Although to this day Marilyn Monroe's death was ruled a suicide, it is reported that Momo sent two of his best hit men to her house on that August 4, 1962. The killers allegedly inserted a Nembutal suppository into her, which caused her death. The plan was for reporters to discover loveletters written to Marilyn by Bobby and destroy the Kennedys "good boy" image. Unfortunately, the plan backfired when Bobby ordered the FBI to keep a tight lid on the investigation and keep the press at bay. The constant surveillance, the Cuban debacle, and now the Marilyn Monroe scandal, or lack thereof, had taken its toll on Giancana. He began telling whomever would listen that he was planning something big against President Kennedy.