Raoul Duke and his attorney Dr. Gonzo drive a red convertible across the Mojave desert to Las Vegas with a suitcase full of drugs to cover a motorcycle race. As their consumption of drugs increases at an alarming rate, the stoned duo trash their hotel room and fear legal repercussions. Duke begins to drive back to L.A., but after an odd run-in with a cop, he returns to Sin City and continues his wild drug binge.

In early-1970s Las Vegas, Sam "Ace" Rothstein gets tapped by his bosses to head the Tangiers Casino. At first, he's a great success in the job, but over the years, problems with his loose-cannon enforcer Nicky Santoro, his ex-hustler wife Ginger, her con-artist ex Lester Diamond and a handful of corrupt politicians put Sam in ever-increasing danger.