It's late at night in a major hospital, and everything is quiet. An old man shuffles down a hall, into an elevator, and right into the office of Dr. Graydon Whitcomb. With an amazing burst of strength and speed, the old man lifts his oxygen tank and swings it at Dr. Whitcomb's head! The next day Monk shows up at the hospital with his own medical emergency: a bloody nose. His seemingly incurable nosebleed leads him to seek out Dr. Whitcomb, the hospital's chief of neurotrauma. Entering Whitcomb's office, Monk bumps into a coffee table, and then into the dead body of Dr. Whitcomb!

It's near midnight and a street musician is getting ready to go home. Unfortunately, it's not the musician's night. As he walks down a dark alley, an attacker emerges and whacks him over the head with a tire iron. But the attacker is not finished. He proceeds to suffocate, poison, stab, shoot, and crush the musician, killing the victim six different ways in all. The man who killed the street musician left a note identifying himself as the "Six-Way Killer," and the note promises that he will strike again in 36 hours. The federal government is taking over the case, and the Deputy Police Commissioner orders Stottlemeyer, Disher, and Monk to assist the man in charge of the federal investigation, Agent Thorpe.

Lt. Disher has decided to resign from the police force after botching a big drug raid. Capt. Stottlemeyer tries to persuade him not to quit, but it's no use. Uncle Harvey left Randy his farm after committing suicide, and Randy has decided to move to the country to start a new life. On the farm, Randy has reservations about the death of his uncle. He calls Monk, and asks if he would come to the farm to investigate. Monk, of course, has reservations of his own. But after a little coaxing from Natalie, Monk decides that he should help his friend Randy, and the next day he's on a bus to the country.

Popular shock jock Max Hudson is doing his morning radio show when he gets a phone call. Across town at Max's house, his wife, Jeanette, has been found dead. In an apparent accident, Jeanette left the gas from her bedroom fireplace on, took a nap, and died of asphyxiation. Jeanette's sister, Linda, goes to Monk for help. Monk agrees to investigate, and after some snooping at Max's house, Monk agrees with Linda that Jeanette's death looks suspicious, and that Max was probably involved. But Max was on the air at the time Jeanette died. How could he have done it?

Monk and Natalie are on a visit to Natalie's parents' house, when the conversation turns to their neighbor, Paul Buchanan. Paul grew up with Natalie and has long harbored feelings for her, but Natalie thinks he is a creep. Natalie's parents explain the circumstances of the recent deaths of Paul's father and stepmother. When Monk questions some of the facts of the story, Natalie suspects foul play. She has a hunch that Paul Buchanan is somehow involved, and hires Monk to look into it.

Gail Segalis and her new boyfriend have just returned home from a trip to Europe. To celebrate their one week anniversary, Gail uncorks an expensive bottle of wine. To her surprise, there’s something inside – but it’s not wine. Her boyfriend, who just stepped out of the shower, flies into a rage and strangles her with a towel! Gail Segalis falls to the ground, dead. The next day, Monk – getting his grocery shopping done – bumps into a fellow shopper. They hit it off immediately. His name is Hal Tucker. Hal is everything Monk ever wanted in a friend, and the two men promise to meet again soon. Back at Gail Segalis’ house, a full crime scene investigation is underway. Monk is there, and it turns out that he knew the victim. Gail was a former police dispatcher who used to car pool with Monk. She would tell him about all the trips she wanted to take, and promised to send him a picture if she ever got to the Parthenon. Then, in the middle of the investigation Natalie receives a call for Monk. It’s his new friend, Hal! Everyone is stunned to hear that Monk has a friend, but Monk couldn’t be happier.

A missing millionaire suffering from leprosy comes out of hiding and hires Monk to recover some papers from his estate. Monk takes the job, and soon finds himself in the middle of a shadowy murder plot worthy of a classic Hollywood film noir.

Monk is preparing to spend a quiet Christmas at home, until his father, Jack, who he hasn't spoken to in 40 years, rolls into town! But dad's not sticking around -- he's a truck driver with a tight delivery schedule. Leaving behind Natalie's holiday party and all that is familiar to him, Monk joins his estranged father on the road. While trying to repair their relationship, Monk discovers that his father is entangled in a dangerous mystery and the two men must put aside their differences to solve the case. Dan Hedaya guest stars as Jack Monk.

When Captain Stottlemeyer's son Jared skips school to attend a rock music festival, Monk and Natalie join the Captain at the festival to help look for him. Monk hates the atmosphere and wants to leave, but soon a roadie named Stork turns up dead of an apparent drug overdose. One of Stork's friends, a fellow roadie named Kendra, insists that Stork was killed. Kendra asks Monk to investigate, and he agrees.

Early one morning, Dr. Kroger's cleaning lady is found stabbed to death in Kroger's office, and the police suspect that one of Kroger's patients could be the culprit. Consumed with the thought that one of his patients would commit murder, Dr. Kroger retires, sending Monk into a complete tailspin and out to uncover what really happened to the cleaning lady.