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.

Joel Barish, heartbroken that his girlfriend underwent a procedure to erase him from her memory, decides to do the same. However, as he watches his memories of her fade away, he realises that he still loves her, and may be too late to correct his mistake.