Adrian Monk (Tony Shalhoub) was once a rising star with the San Francisco Police Department, legendary for using unconventional means to solve the department's most baffling cases. But after the tragic (and still unsolved) murder of his wife, the devastated Monk became obsessive-compulsive. His psychological disorder has caused him to develop an abnormal fear of virtually everything: germs, heights, crowds... even milk. Monk's condition eventually cost him his job, and continues to pose unique challenges in his everyday life.

Those daily challenges eventually forced Monk to hire a personal nurse, Sharona Fleming (Bitty Schram), who was always there to offer her assistance when even the simplest of tasks (like organizing his sock drawer) became an angst-ridden ordeal for Monk. Along the way, Sharona also became Monk's own "Girl Friday," an unlikely Dr. Watson to his Sherlock Holmes.

When Sharona moved back to New Jersey with her son to re-marry her ex-husband, Monk once again became unable to function in his day-to-day life, let alone solve crimes. He slowly comes out of his funk when he meets Natalie Teeger (Traylor Howard), a single mom and bartender who enlists Monk's help when her home gets broken into twice within a week. Monk takes on her case only to find that the more time he spends with Natalie and her young daughter, the more he feels a connection with her - one that is reminiscent of his special relationship with Sharona.

Now working as a private consultant, Monk continues to investigate cases in the most unconventional ways. Although Monk is no longer a member of the police force, his former boss, Captain Leland Stottlemeyer (Ted Levine) still often calls upon him to provide unique insights into cases that have the cops stumped. Stottlemeyer himself is a highly decorated detective, but he knows he will never be as good as the illustrious Monk... and it drives him crazy. Meanwhile, Lieutenant Randall Disher (Jason Gray-Stanford) aspires to be the department's new go-to guy, and relishes every opportunity to bolster the ego of his commanding officer.

Monk is a detective afraid of the dark, a gumshoe afraid of gum. He has no problem cracking a case - as long as it doesn't involve heights or germs, and is in close proximity to his apartment. He'd like nothing more than to gain back his position on the San Francisco police force, but can he pull himself together and get back to solving crimes full time?