Richard Kimble is falsely convicted of his wife's murder and given the death penalty. En route to death row, Kimble's train derails and crashes, allowing him to escape and begin a cross-country search for the real killer, a "one-armed man". At the same time, Dr. Kimble is hounded by the authorities, most notably dogged by Police Lieutenant Philip Gerard.

Årtier efter sin fængsling tilbyder en seriemorder at hjælpe med at løse en række mord – men kun hvis hendes søn, som nu er politimand, vil arbejde sammen med hende.