Eighteen months have elapsed since the conclusion of Day 3. A commuter train bound for Los Angeles explodes. A man steals a suitcase from a passenger in the wreckage and then kills him. Jack has been dismissed from CTU and now works for Secretary of Defense James Heller. Jack is involved with Heller's daughter, Audrey, and their relationship is growing serious. Jack is in LA for a meeting with CTU Director Erin Driscoll, who fired him a year ago, but he finds himself alienated at CTU by Driscoll and the new staff when reports of a possible terrorist strike come in. A young computer hacker named Andrew Paige sees something that he shouldn't on the Internet. Suddenly, he finds himself running for his life as he is pursued by terrorists. Luckily, he is able to warn Chloe O'Brian before its too late. The Turkish Araz family are not what they seem and it becomes clear that they are heavily involved with the day's events. Meanwhile, Heller has a confrontation with his estranged son. Jack finds that Chloe is his only ally as he tries to prove that the train explosion is merely a diversionary target.

NorBAC has been taken over by a joint command to deal with a catastrophic smallpox scenario. Bob (Dmitry Chepovetsky) tries to find a cure for his dog that is suffering from histiocytosis. Jill (Sarah Strange) comes clean with David (Peter Outerbridge) about taking medication for her panic attacks. David discovers that the earlier "Miranda Virus" outbreak might be linked to the U.S. government's secret bio-chemical lab and that whoever manufactured the "Miranda Virus" may possess another, even more lethal, biological weapon.

Jack pushes Driscoll to reinstate him in the wake of Heller's kidnapping. He finds himself working as a subordinate when the Field Ops team goes to pick up Andrew. Behrooz finds himself torn between his loyalty to his parents and his feelings for his girlfriend as he is sent on his first assignment. Heller tries to comfort his daughter as his captors broadcast their intensions on the Internet.

The team re-opens the case of Matthew Adams, a teen-aged cult member who apparently committed suicide back in 1978, when his sister comes forth with new evidence about the deprogrammer her family hired to rescue her brother.

When a lone gunman decides to commit murder inside the morgue, Jordan wonders if there is a connection to any of the recent admits. Where this case leads will cause Woody to dive deep into a world he does not know... to find the truth.

Edie organizes a neighborhood search for the missing Mrs. Huber, just as the absent busybody's sister Felicia Tilman (guest-star Harriet Sansom Harris) arrives on Wisteria Lane. Meanwhile, Bree resigns herself to her marital state and asks an attractive pharmacist (Tony Award-winning actor Roger Bart) on a date; Susan's ex, Karl (guest-star Richard Burgi), suddenly reappears in her life; Lynette fears that Tom is attracted to the new nanny (guest-star Marla Sokoloff); and Gabrielle sinks to new depths - she gets a job.

Goren matches wits with a one-time chess prodigy who has become a fugitive when the body of a young woman is found tossed in the trash.

A Sudanese native wants to sue the U.S. government for the lack of action taken against the mayhem happening in his country and Paul looks to Lori to take the case. Founding partner Shirley Schmidt arrives with a mission to bring order to the firm. While making herself known, she has to deal with Denny who does not want her there, help with Lori's extremely high profile case, and learns that she has to keep her eye on Alan. Alan ends up defending a man who killed his mother in a fit of rage but by accident.

As the spiritual powers of Ben Hawkins evolve, the entity Management reveals it's identity to Ben, (the Russian soldier in Ben's dreams) and then exposes him to a vision of the cataclysmic disasters (a nuclear explosion) that awaits the world if Ben doesn't identify and conquer his nemesis: Brother Justin, the creature of darkness. In order to do this, Ben must find his father, the elusive Henry Scudder, who holds the knowledge of the preacher's identity and location. In the aftermath of the fire which killed Apollonia, Samson covers for Ben by claiming that he died in the fire to get rid of the Texas Ranger still hanging around the troupe, and Samson helps Ben hide the dead body of Professor Lotz, while Lila becomes concerned for the missing Lotz well being. A distraught Sofie runs away, leading a guilt-ridden Jonesy to assemble the carnies to go out looking for her. Meanwhile, Brother Justin's radio sermon has employed two new 'apostles'; an occultist named Wilfred Talbot Smith, who aids Justin that he must kill Henry Scudder to become a true immortal, and a prison inmate named Varlyn Stroud whom is also 'called' by the mesmerizing Justin's voice. Reporter Tommy Doyle continues to investigate the Chin's ministry fire, while Justin and his sister Iris use the radio to continue to spread the word, drawing throngs of weak and impoverished masses into their spiritual web, while Reverend Balthus suffers from a stroke.

Huff grapples with the dangers of psychiatry when a young, eager and attractive pharmaceutical rep does her best to persuade him to aggressively prescribe. But Beth discovers an item in Izzy's closet that may be alarming enough to distract him from his flirtation. Over in the land of Russell, Huff's lawyer friend may be the victim of federal surveillance or simply the victim of his own paranoia.