Monk was a brilliant homicide detective working for the San Francisco Police Department until his wife Trudy died in a car bomb attack in 1997 while picking up cough medicine for Ambrose. Monk suffered a nervous breakdown and became a shut-in, refusing to leave his house for three years. With the help of practical nurse Sharona Fleming (Bitty Schram), he was finally able to leave the house. He began to perform consulting work for the police on particularly difficult cases.

Captain Leland Stottlemeyer (Ted Levine) and Lieutenant Randall "Randy" Disher (Jason Gray-Stanford), call on Monk when they can't crack a case. Stottlemeyer is often infuriated by Monk's disorder, but respects his friend and former partner's amazing observational abilities, as does Disher. Monk's obsessive attention to detail allows him to spot tiny discrepancies, find patterns, and make connections that everyone else in an investigation misses. Monk continues to search for information about his wife's death, the one case he has been unable to solve.

In the third season, Sharona decides to re-marry her ex-husband and moves to New Jersey. Natalie Teeger (Traylor Howard), a single mother with a daughter about twelve years old, is soon hired as Monk's new assistant.

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