Bitty Schram, who portrayed Monk's first assistant, Sharona Fleming, left the series in the middle of season 3. Traylor Howard was subsequently brought in to portray Natalie Teeger for the remainder of the series. Stanley Kamel, who portrayed Dr. Charles Kroger, Monk's therapist, died of a heart attack in April of 2008 during the production hiatus in between the sixth and seventh seasons. His character was replaced by Dr. Neven Bell, portrayed by Hector Elizondo, for the remaining two seasons.

Despite their names seen in the opening credits, Ted Levine and Jason Gray-Stanford had occasional absences in a few episodes of the series. Subsequently, this meant that the only cast member to appear in every single episode of the series was Tony Shalhoub.

Warrick Tennyson was a career criminal and explosives expert who was hired to build the bomb in 1997 which killed Trudy (Monk's wife).

Dale the Whale tells Monk that Tennyson was involved in the murder in "Mr. Monk Goes to Jail" and tells Monk he can find Tennyson in New York. Monk goes to New York in the next episode, "Mr. Monk Takes Manhattan", in hope of answers, but finds that Tennyson is dying of heart disease and kidney failure. Because he’s being questioned in connection with a Federal racketeering case, the District Attorney is not letting anyone else see him. The only way for Monk to get access to Tennyson is to solve the recent murder of the Latvian Ambassador.

Having cracked the case, Monk's party is allowed to visit Tennyson (Collison) on his deathbed. Tennyson remembers being hired by a man to build the bomb that killed Trudy. When asked, he says he doesn’t know the name or the description of the man that hired him, since it was dark when they met, and it looks like Tennyson is a dead end. But Tennyson remembers one vital clue: the man had six fingers on his right hand.

Monk asks for a few moments alone with Tennyson. When the others are gone, Tennyson asks for forgiveness, but Monk cannot bring himself to give it. He turns off Tennyson's morphine drip. But a few tense moments later, he says, "[T]his is Trudy, the woman you killed, turning it back on," and does.

The gang prepare to leave New York, having gotten at least one step further in solving Monk’s most important case.

"Mr. Monk Is On The Run (Part One)"

Frank Nunn was a career criminal who was hired by a mysterious figure known as "The Judge" to assassinate Trudy Monk. Nunn hired Warrick Tennyson, an explosives expert, to build and plant the bomb, while Nunn detonated it with a cellular phone.

Twelve years later, he was hired to build another bomb, as part of a scheme by Dale Biederbeck, and plant it in the back of a car meant to be ridden by the Governor of California and his wife during his hometown's bicentennial parade.