Dr. Mark Sloan is chief of internal medicine at Community General Hospital in Los Angeles and a L.A.P.D. consultant, Sloan has a knack for getting into trouble, negotiating the twists and turns of mysteries and solving crimes with the help of his homicide detective son Steve.
When George Lawson, a former medical student who of Mark's, was diagnosed with schizophrenia is found at a murder scene without an alibi, Mark, Jesse, Steve, and Steve have the large task of proving he had nothing to do with the crime. Through the course of their investigation, Mark discovers that the jilted wife of the man who was having an affair with the victim's wife knows more than she's letting on about what happened. As a result, they turn to George and his coded messages for help in solving the crime.
After Steve gets in a bad accident and is saved by Jesse, he has to spend a few days in the hospital to recover. However, still slightly under the effects of anesthesia, Steve witnesses what he believes to be a murder and tries to get Mark and the others to believe what he saw. He then begins to investigate and soon discovers that the murder involves a respected doctor who appears to have a few secrets he was trying to keep hidden.
One of Mark's med students, Alex, is a contestant on a Big Brother type reality show, hoping to win the grand prize so he can use it to pay off his student loans. When a fellow contestant ends up murdered, Mark takes the victim's spot on the show, with the hopes to find out the killer, he finds out the real reason why the contestant was targeted and how the killer almost got away with their crime.
When two fashion designers hold their wedding on the catwalk before a show, things turn explosive when a bomb goes off and ultimately kills the groom. Through the course of Steve and Mark's investigation, they soon discover that the reason why the groom was targeted had to do with his planning on turning state's evidence in a drug kingpin's upcoming trial and that one of his models might know more than she's letting on.
After an elderly misanthrope dies at Community General, Jessie and Amanda find themselves in a unique situation – heirs to the old man's fortune with four other people. However, there's a catch: the will is set up in the form of a "tontine," going to the last surviving heir. As a result, all the heirs start having mysterious accidents, and ultimately all but Jesse and Amanda end up dead. Before an apparent killer can turn their sights on to his friends and colleagues, Mark aids Steve in finding out whether the old man had a living relative who was trying to get their hands on the fortune.
E22
A filmmaker friend of Alex convinces him to let him work on a documentary about a nurse who disappeared from Community General twenty five years ago under mysterious circumstances. When the filmmaker goes to Mark with blood found in the course of his investigation, they soon suspect that the hospital could be haunted and that the filmmaker has a connection to the nurse.
E17
A murder an attack at his beach house prompts Mark to investigate a hospital staff member who was having an affair with the deceased's young wife.
After Amanda wins an elite Medical Examiner's award, she, Mark, and Jesse have to investigate who deliberately let loose a deadly disease inside the upscale hotel where the award ceremony was going to take place.
Following the deaths of several patients and an unpopular doctor at Community General Hospital, Steve, Mark, and his colleagues work on trying to discover what connects all the deaths. When the doctors soon discover the connection to all the deaths – each victim previously survived a near death experience – they have to find out who the killer is before they carry out their next murder, and they have their sights set on Steve.
When a young man with a chip on his shoulder named Tommy gets in a scuffle at BBQ Bob's, Steve arranges it so Tommy complete his community service at a local boxing club for at-risk youth. When a fellow boxer takes his own life in front of Tommy, he turns to Steve and the owner of the boxing club for help in discovering why the boxer was behaving so erratically when he died.
Steve and Mark work to aid two women detectives on the LAPD who are investigating a group of crooked cops who are targeting unethical businessmen in order to donate their organs to those in need.
Dr. Sloan insists that a man he helped condemn for serial bombings is guilty. Even after a post-execution explosion.
Dr. Sloan leads an unauthorized investigation into the rash of bombings around Los Angeles.
E15
E16
While guest starring on a weekly local television show, Mark soon uncovers that working on the radio and television can be deadly when an local notorious shock jock is found murdered and it appears that the host of the show he's appearing on is high on the list of suspects.
E1
Mark's investigation of a hit-and-run death leads him to a priest; Mark is criticized for treating an elderly patient for free.
E4
A millionaire plans to leave his fortune to the hospital but dies, Dick Van Dyke has multiple roles in the episode.
Illusionist Eddie Clark, friend and a patient of Mark, stops by the hospital with tickets for his last show at the Magic Mansion. When Mark and his guests arrive, they soon discover that Eddie's partner Paul intends to leave their partnership and take all their tricks with him. Later in the evening, Paul is found murdered and Eddie is considered the prime suspect. As a result, Mark turns to Jack, Amanda, and Steve's help to prove Eddie's innocence, and as result, decide to hold their own impromptu magic show to help him out.
Dr. Sloan is caught in a police vie raid when he investigates the murder of a prostitute whom he once treated for mysterious bruises.
Sister Michael, a nun at the nearby convent, played by former Sugarbaker diva Delta Burke, enlist the help of her friend, Mark Sloan, to solve a murder that took place at the convent. Mark goes undercover as a priest in an effort to find out who killed the nun's friend, a young producer who did a video for the church.
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