An investigation into a video of an alien autopsy puts Mulder and Scully in the middle of a conspiracy involving WWII Japanese scientists brought to America to continue their experiments which may shed light on Scully's abduction.

Mulder is trapped inside a train car which contains a suspected alien-human hybrid and also a bomb, while Scully pursues the truth about her abduction and the mystery behind the implant in her neck.

A French salvage ship searching for a lost WWII fighter plane unknowingly surfaces an alien which appears in the form of black oil and has the ability to jump hosts. Mulder heads to Hong Kong to investigate the salvage broker who sold the information to the French and he encounters Krycek, who has been selling information from the MJ documents. As Mulder prepares to take Krycek back to the US, the alien makes its way to Hong Kong and takes control of Krycek.

Mulder pursues Krycek (unaware of the alien that has taken over his body) to get back the DAT tape containing the MJ documents. Meanwhile, the shooting of A.D. Skinner uncovers evidence that could lead Scully to her sister's murderer.

After his mother suffers a stroke under strange circumstances, Mulder searches for a strange, benevolent alien man that possesses miraculous healing powers. With the help from Mr. X, he learns about the involvement of the Cigarette-Smoking Man and uncovers some secrets kept by his parents.

With his mother on a deathbed and the alien bounty hunter in pursuit, Mulder decides to put Jeremiah Smith, the alien healer, in mortal danger for a chance to finally uncover the whole truth behind the alien conspiracy. Meanwhile, the Syndicate suspects that they have a traitor in their midst and set up a trap.

Mulder is given a tip about potentially dangerous paramilitary operations on the U.S. soil but during the sting operation is surprised to find out the identity of his mysterious informant - it turns out to be Alex Krycek. Suspicious about his true motives, Mulder reluctantly follows the information provided by Krycek. However, soon he discovers a much bigger conspiracy which takes him to a gulag in Tunguska, Russia where prisoners are being used for experiments involving a substance of alien origin.

While imprisoned in Russia and infected with the Black Cancer, Mulder learns that Krycek is working with the men responsible and everything has been a setup from the start, while Scully and Skinner are called to a suspicious Senate hearing where the only question is the whereabouts of Agent Mulder.

Scully's recent failing health is revealed to be an inoperable cancer in her skull, which appears to be common among abductees and she attempts to come to terms with her condition. Meanwhile, Mulder and the Lone Gunmen break into a high-security research lab to find the cure that could save her life.

While celebrating Scully's 33rd birthday, a strange woman informs Mulder that NICAP member Max Fenig (see Fallen Angel) has recently died in a plane crash. After a visit to the crash site and finding Max's body with radiation burns on it, Mulder suggests that the plane was intercepted by a UFO and is rapidly being covered up by the military.

Mulder is arrested for investigating the plane crash and interfering with a military operation, while Scully is caught in an attempted assassination of Corporal Frish which claims the life of Agent Pendrell. Scully bails Mulder out of prison, and they go to Max Fenig's trailer to find out why he was on the plane. Mulder finds evidence of alien technology and boards a plane with it, but the plane is intercepted mid-flight and it disappears. Mulder is again left with nothing.

After a swarm of bees mysteriously kill a postal worker in an enclosed restroom, Assistant Director Skinner covers it up by destroying the evidence. In order to complete the task he poses as Agent Mulder, however his deception backfires. When Mulder finds out and confronts him, Skinner reveals that he is working for the Cigarette-Smoking Man in order to obtain a possible cure for Scully's cancer.

Mulder fights to prove that a discovery frozen in the mountains of Canada is an irrefutable evidence of alien life, but his quest for the truth only leads to more lies and an unthinkable conclusion.

Scully helps Mulder fake his own death in order for him to go undetected through the Department of Defence and find out the answers to his new questions about the government hoax concerning the existence of extraterrestrial life. Meanwhile, at a joint FBI/DOD inquiry, Scully's attempt to drive out the Conspiracy's informant is halted as her cancer takes a bad turn.

The Cigarette-Smoking Man helps Mulder to obtain Scully's cure and also lets him see his real sister who doesn't turn out to be as happy to see Mulder as he would've liked. In return for this, the Cigarette-Smoking Man asks that Mulder quit the FBI and work for him in the Syndicate where he could have power and respect which Mulder turns down, deciding to stay on the side of justice. While Scully's cure appears to have worked, the Cigarette-Smoking Man faces his own enemies and disappears, presumed dead.