Captain Stottlemeyer and Lieutenant Disher are making a routine arrest when a mysterious man in a car drives up and shoots at them, wounding Stottlemeyer. With Stottlemeyer in the hospital, Monk joins Disher in an intense investigation. Their prime suspect is the man Stottlemeyer and Disher were trying to arrest at the time of the shooting, a biker who was attempting to skip bail. When Monk and Disher try to apprehend the biker, Monk's obsessive-compulsive disorder allows the suspect to escape.
Consumed with guilt, Monk goes to Dr. Kroger for help. Dr. Kroger gives Monk some pills that help people with O.C.D., and Monk reluctantly tries them. The pills work, and soon Monk becomes a completely different person. He's more relaxed, and his fears and phobias seem to be gone. But despite the benefits, there's one key cost: Monk has lost his ability to solve crime. With Captain Stottlemeyer's shooter still at large, the police desperately need the "old" Monk's help on the case.
But Monk is enjoying his new personality, and no one can convince him to stop taking the medication. Finally, Monk makes a realization: the medicine interferes with his ability to envision his late wife, Trudy, a side-effect that Monk cannot tolerate.
Monk stops taking the medicine, and quickly gets back on the case. The police have determined that the biker was not involved in the shooting. Searching for another explanation, Monk makes a connection between the shooting and a suicide that happened nearby at approximately the same time. Monk deduces something very important about the suicide note found at the scene: it wasn't written by the suicide victim!
It turns out that the woman who killed herself left a note telling of her ex-husband's plan to rob an armored car. She told the ex-husband, a man named Lester Highsmith, about the note before she jumped. Highsmith rushed to the scene of the suicide to destroy the suicide note, but the police had already arrived by the time he got there. So he shot at the Captain to divert the police from the suicide scene, giving him time to replace the incriminating note. The mystery solved, Monk and Sharona rush to intercept Highsmith before he can successfully complete his armored car heist.
In the end, Monk throws away the medication. Too bad for the criminals of San Francisco!