Leonard Shelby is tracking down the man who raped and murdered his wife. The difficulty of locating his wife’s killer, however, is compounded by the fact that he suffers from a rare, untreatable form of short-term memory loss. Although he can recall details of life before his accident, Leonard cannot remember what happened fifteen minutes ago, where he’s going, or why.
Whilst on a short weekend getaway, Louise shoots a man who had tried to rape Thelma. Due to the incriminating circumstances, they make a run for it and thus a cross country chase ensues for the two fugitives. Along the way, both women rediscover the strength of their friendship and surprising aspects of their personalities and self-strengths in the trying times.