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.

Upon his release from prison, Verne Miller works his way into Al Capone's organization. He becomes a top assassin and earns Capone's trust. However, Miller's failing health and an over-sized ego get him into trouble with the law and Capone.