After Mulder’s disappearance, Scully returns to FBI headquarters to find Special Agent John Doggett heading up a FBI manhunt for her partner. Knowing that type of search will prove futile, Scully and Skinner turn to the Lone Gunmen in hopes of uncovering information about additional UFO activity around the time of Mulder’s disappearance. Although such information leads them to Gibson Praise, the man with Gibson, a man who appears to be Mulder, is in fact an alien bounty hunter. Finally realizing that Mulder will not be found so easily, Agent Doggett is officially assigned to the X-Files. Now, after all she has been through with Mulder, it is Scully who is “the believer” and who must find a way to work with “the skeptic,” John Doggett.
Newly appointed Deputy Director Kersh organizes a manhunt for Mulder and assigns Agent John Doggett to head the team. Scully and Skinner go along with the investigation but are warned by Kersh that they will be fired if anything is said about aliens. Scully, along with the Lone Gunmen, surmise that the Bounty Hunter is trying to erase all evidence of abductions, and they realize that he may be going after Gibson Praise, who is now living at a school in Arizona. Agent Doggett comes to the same conclusion and his team race Scully and Skinner to the school where they find Mulder trying to kidnap Gibson.
As the search for Mulder intensifies in the Arizona desert, Gibson Praise leads Scully to believe that she is truly closer to her target. Meanwhile, A.D. Kersh informs Agent Doggett that he has been assigned as Mulder's successor on the X-Files.
While tackling his first X-File case about a series of gruesome murders surrounding a bat-like creature, Doggett quickly learns that his investigative techniques are somewhat dissimilar to Scully's.
Scully evades Doggett's help in investigating a vicious murder in a remote area of Utah, and she is trapped in the small town by a religious cult that believe a slug-like creature is the second coming of God who needs a human host to survive.
In 1990 a little boy inexplicably disappeared from his crowded school playground and was never seen again until now, ten years later, and he hasn't aged a day.
A prominent lawyer wakes to find himself in jail and about to be prosecuted for the murder of his wife. He has no memory of this event however, and when the days begin to regress backward towards the murder, he realizes that he has been given a second chance.
Working without Scully's input, Doggett and Skinner try to stop the mysterious murder spree of a drug-induced religious cult leader, and it becomes clear that the man can enter the dreams of the people he knows and can kill them in their sleep.
When a real estate agent is shot inside a prison cell by someone who apparently fired from the roof, Scully and Doggett track him to two exterminators, one of whom has x-ray vision.
A man whose blood is rapidly changing into metal alloy enacts revenge on those who caused his condition.
An Indian mystic whose son died in a chemical plant accident smuggles himself into the United States and takes his revenge on two families in suburban Washington, D.C.
Doggett comes upon an old case that Mulder kept secret from Scully and he follows up the investigation, hoping to find a possible connection to Mulder's disappearance.
Scully and Doggett must race against the clock to investigate and fight off a contagion lurking in the subway tunnels of Boston.
When Scully and Doggett are contacted by a man who claims his wife was murdered shortly after giving birth to an alien baby, Scully digs deeper into reports of alien fertilization on humans, and she begins to question her own pregnancy and its conception.
When Teresa Hoese (the woman Scully and Mulder met the previous spring in Oregon just before Mulder was abducted) is found in a desert after enduring alien testing, Doggett alerts Scully that this could have something to do with Mulder and his whereabouts. Skinner joins them and they travel to the hospital where Teresa is clinging to life by a thread, and Scully realizes that this is exactly what's going on with Mulder.
Shortly after Mulder is buried, Billy Miles is found very dead, but he somehow comes back to life. Skinner and Scully put all their hopes into digging up Mulder and discovering that he too, is still alive. As Mulder lies in the hospital without indication that he is going to fully recover, Krycek comes to Skinner and offers him a vaccine to the virus that has infected Mulder, but the cost of the vaccine is that Skinner has to kill Scully's unborn child.
Mulder's request for reassignment to the X-Files is denied by Kersh, who hopes that Mulder will simply quit the FBI. When a census worker is killed on the White House lawn trying to get information to the President, Mulder gets in over his head trying to discover what the man knew.
Special Agent Reyes enlists Mulder's help in investigating a supernatural killer's connection to the unsolved murder of Agent Doggett's son, Luke.
Mulder and Doggett are reluctantly thrown together to investigate several deaths aboard an oil rig, and Mulder becomes convinced that the rig is really carrying the black oil alien.
While Scully takes maternity leave, Doggett is partnered with a young agent who is fascinated with the X-Files and has followed Mulder and Scully's careers. She and Doggett investigate the death of an old man and the disappearance of his son, but when they disappear as well Mulder heads out to search for them.
Mulder and Doggett join forces to investigate the arson attack on a genetics lab where one of the doctors suspected of experimenting with alien impregnation is killed. They encounter Billy Miles, who has been changed into an alien replicant after his recent abduction and is attempting to erase evidence of the tests. When a woman helping Scully out at home is found to be a part of the conspiracy, the agents, along with Monica Reyes and Alex Krycek, know they must protect Scully and her baby from Billy Miles and get her out of the city.
Mulder, Doggett and Skinner attempt to fight off the alien replicants, and they find a connection to the conspiracy that leads into the FBI while Reyes and Scully head to a remote farm to safeguard the birth of Scully's child.