A successful jazz musician whose marriage is on the rocks, a man in black who threatens to expose him, a young mechanic with links to a mobster, and the mobster's moll are all riders on the lost highway, trapped in their worlds of desire, destiny and unknown destination.

Rolfe is the dwarf brother to a normal-sized Steven. When Steven's girlfriend Carol becomes pregnant, the pair are fearful that the baby will inherit the dwarism gene. Matters are complicated still further when Carol finds herself falling in love with Rolfe.

Clarence meets Alabama. He then proceeds to accidentally kill her pimp. The two get married and acquire an unexpected wedding present - a suitcast full of cocaine. They hit the road and end up in Los Angeles, where they intend to sell the drugs and have enough money to live off. But, unknown to them, ruthless gangsters are on their tail, determined to reclaim their lost property.