Shalhoub was born in the Midwest, attended college in Maine and studied theater at the Yale School of Drama. He spent four seasons at the American Repertory Theatre in Cambridge, MA, appearing in such productions as "School for Scandal" and "The Three Sisters.” Shalhoub went to New York, where he appeared in productions at the New York Shakespeare Festival and made his TV debut playing a terrorist in an episode of "The Equalizer" (CBS, 1986). By 1987, he had guest starred on an episode of "Spenser: For Hire" and the following year made his TV-movie debut in "Alone in the Neon Jungle" (CBS). He played Enrico Fermi in "Day One" (CBS, 1989), the Emmy-winning drama about the Manhattan Project. From 1991-97, he played the romantic cab driver on "Wings.” Shalhoub's career received a boost in 1992, with his Tony-nominated portrayal of a Jewish man looking back on his life in the Broadway production of Herb Gardner's "Conversations with My Father.” Other stage credits include the female version of "The Odd Couple,” with Rita Moreno and Sally Struthers, and Wendy Wasserstein's "The Heidi Chronicles,” opposite Brooke Adams.

In 1990, Shalhoub made his feature film debut as a doctor in Norman Rene's "Longtime Companion,” but it was his memorable turn as a New York cab driver speaking an unidentifiable language to Bill Murray in "Quick Change" (1990) that caught the audience's attention and demonstrated the actor's gifts for comic dialects. He went on to appear as an over eager film executive in the Coen Brothers' "Barton Fink" (1991) and a chess club member in the underappreciated "Searching for Bobby Fischer" (1993). With his performance as Primo, the temperamental immigrant chef in "Big Night,” Shalhoub demonstrated a wide range of emotions, from indignation (at a customer's request for spaghetti) to infatuation (with the local florist played by Allison Janney). His delicately shaded, nuanced portrayal earned him critical praise.

He quickly became in demand, filming supporting roles in three 1997 features: the sci-fi thriller "Attica,” as a DNA broker; Barry Sonnenfeld's "Men in Black,” as Jack Jeebs, an alien who has assumed human characteristics (a role he reprised for the 2002 sequel) and Danny Boyle's "A Life Less Ordinary,” as a bartender. The following year, he re-teamed with Tucci for "The Impostors,” playing the first mate of a luxury liner. Shalhoub had by then graduated to film's character actor A-list, with supporting roles in films such as "Primary Colors" (1998), "The Siege" (1998), "A Civil Action" (1999), "The Tic Code" (2000) and "Thirteen Ghosts" (2001) and would turn in particularly outstanding performances as an anxiety-ridden sci-fi actor taken on a real-life intergalactic adventure in the winning comedy "Galaxy Quest" (1999), as Freddy Riedenschneider in the Coen Brothers' stylish noir send-up "The Man Who Wasn't There" (2001) and as Alexander Minion in all three of director Robert Rodriguez's "Spy Kids" films.

The actor's attempt to return to series television in the sit-com "Stark Raving Mad" (NBC, 1999-2000), playing the blocked horror author Ian Stark who plays morbid jokes on his uptight young editor (Neil Patrick Harris), was received tepidly by critics and viewers, but Shalhoub found the role of a lifetime when he was cast in the lead role of Adrian Monk, a former San Francisco police detective who suffers from an extreme case of obsessive-compulsive disorder and a variety of phobias since the murder of his wife but remains a brilliant crime-solver, for the USA Network comedy-mystery TV movie "Monk" (2002), which became a similarly-named series (2002- ) airing on USA and, subsequently, ABC. In 2003, Shalhoub would win both a Golden Globe and an Emmy as lead actor in a comedy series for his portrayal of the quirky detective, followed by another Emmy victory in 2005. Shalhoub continued to be a strong supporting presence in feature films, with roles in "Against the Ropes" (2004) as Jackie Kallen's (Meg Ryan) cutthroat nemesis, boxing impresario Sam LaRocca, and the Hollywood crime comedy "The Last Shot" (2004).

In 2006, Shalhoub won the Emmy again for Outstanding Lead Actor in a Comedy Series for “Monk,” beating out such stiff competition as Steve Carell (NBC’s “The Office”), Larry David (HBO’s “Curb Your Enthusiasm”), Kevin James (CBS’s “The King of Queens”) and Charlie Sheen (CBS’s “Two and a Half Men”). As popular as ever entering into its fifth season, “Monk” continued to be one of cable’s most celebrated original series, earning Shalhoub yet another Emmy nomination – his fifth – on July 19, 2007.