In Los Angeles at the turn of the 1970s, drug-fueled detective Larry "Doc" Sportello investigates the disappearance of an ex-girlfriend.
When a shipment of heroin disappears between Italy and New York, a small-time pimp in Milan is framed for the theft. Two professional hitmen are dispatched from New York to find him, but the real thieves want to get rid of him before the New York killers get to him to eliminate any chance of them finding out he's the wrong man.
Government agent Sol Madrid travels to Mexico with hooker Stacey to bring mobster Villanova and drug kingpin Dietrich to justice.