Former police detective Adrian Monk (Tony Shalhoub), whose photographic memory and amazing ability to piece together tiny clues made him a local legend, has suffered from intensified obsessive-compulsive disorder and a variety of phobias since the unsolved murder of his wife, Trudy, in 1997. Now on psychiatric leave from the San Francisco Police Department and working as a freelance detective/ consultant on difficult cases, Monk hopes to convince his former boss, Captain Leland Stottlemeyer (Ted Levine), to allow him to return to the force. Stottlemeyer, who wavered between admiration for Monk and annoyance at his eccentricities during the first season, is becoming more of a friend to Monk as the series develops, frequently calling him in to help, as much for Monk's benefit as for his own. However, he knows Monk's limitations as well as his strengths and may still harbor doubts about the wisdom of allowing Monk to carry a gun or subdue a perpetrator. Stottlemeyer's second-in-command, Lieutenant Randall Disher (Jason Gray-Stanford), also seems to be developing both admiration and compassion for the man he once labeled "the defective detective."

Despite flaws and inadequacies all around, the three are becoming an increasingly effective team, with additional help from Monk's personal assistant. From the double-episode pilot through the first half of season three, Monk was aided by his nurse, Sharona Fleming (Bitty Schram). But in the tenth episode of the third season, Sharona was replaced by a new assistant, Natalie Teeger (Traylor Howard). Like Sharona, a divorcee with a son named Benjy, Natalie is a single parent, a widow with a daughter named Julie (Emmy Clarke). Unlike Sharona, Natalie is not a nurse but a former bartender with a fresh perspective on "Mr. Monk," as she still addresses her new boss.