Tony Accardo have taken the reins of the criminal empire built by their mentor Al Capone. Thanks to Sam Giancana's takeover of the policy racket, the gangsters are now making millions. With so much money coming in, Accardo knows they need a place to hide it. They find their answer in a growing city where gambling is now legal: Las Vegas. However, the New York mafia is already there, led by criminal mastermind Meyer Lansky.

Tony Accardo receives a phone call from Joseph P. Kennedy, asking the mob kingpins to use their pull with the Illinois union vote to help his son, John F. Kennedy, win the upcoming presidential election. In return, he offers to put an end to his son Robert F. Kennedy's investigation into Giancana and the Outfit. As election day nears, Kennedy's fight against Richard Nixon tightens, turning Illinois into a key battleground. Giancana delivers the union votes. After a close race, Kennedy is declared the victor. Just weeks after Kennedy takes office, his brother Robert is named Attorney General. To the Chicago mob's surprise, when Robert takes office as the new U.S. Attorney General in 1961, he makes his top priority going after organized crime ó and one of his primary targets is the Outfit. Weeks after, John F. Kennedy is shot and killed in Dallas. After his brother is assassinated, Robert steps down from his post as Attorney General and the investigation into organized crime is virtually dropped. The government begins an investigation into the assassination, with rumors already circulating that the mafia could have been involved.

After becoming the most powerful mob boss in the country, Al Capone now finds himself locked up in America's newest and harshest maximum security prison: Alcatraz. Prohibition has recently been repealed and one of the Outfit's most important sources of income dries up. With Capone cut off from all communication, his most trusted men, Frank Nitti, Tony Accardo and Paul Ricca, must keep his organization from collapsing. With Americans flocking to theaters by the thousands, the movie business is raking in millions of dollars a month. To take advantage of Hollywood, Nitti recruits Willy Bioff. Acardo breaks into a new racket in Chicago: slot machines. With help from Ricca, Accardo builds a network of slots in Chicago bars, earning up to $20,000 a year. By the end of 1939, the Outfit is bringing in more money than ever before... But new problems start to appear.

Richard Dawkins examines the growing suspicion the public has for science-based medicine, despite its track record of successes like the germ theory of disease, vaccines, antibiotics and increased lifespan. He notes a fifth of British children are currently not immunised against measles, mumps and rubella, attributing it to fears arising from a highly controversial report linking the vaccine with autism. Dawkins criticizes the growing field of alternative medicine which does not pass the same objective and statistical rigour as scientifically derived treatments using controlled double-blind studies. Without verifiable evidence, alternative therapies must rely on biased anecdotes and word of mouth to perpetuate. Dawkins observes these treatments have fanciful rationales and rituals behind them, with many alternative treatments employing pseudoscientific jargon such as "energy", "vibration" or "quantum theory" to give themselves greater credence to patients.

Rejected by Vorenus and Eirene and racked by guilt for the killing of Eirene's fiancé out of a jealous rage, Pullo has sunk to working as an assassin for the gangster Erastes. When Pullo gets arrested for killing one of Caesar's popular opponents, he condemns himself by refusing to name who hired him, despite Octavian's attempts to defend him.
Meanwhile, Vorenus finds his new official duties as magistrate tedious, especially when he gets caught between Caesar and the demands made by veterans' spokesman Mascias.

In the sixth episode, Steven's attorneys cross-examine forensic experts about contaminated evidence and the absence of proof linking Steven to the crime.