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.

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.

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.

Mulder and Scully meet Cassandra Spender, a woman who claims to be a multiple abductee and wants to deliver a positive message about the aliens. Mulder's new found disbelief in extraterrestrial activity is enhanced while Scully forms a special bond with the woman. A series of group attacks against abductees take place and the shadowy Syndicate believes that a rebel alien resistance is attempting to destroy all their work.

After the gathering at the abduction site where everyone is killed by the rebel bounty hunters, Cassandra Spender disappears and Mulder is blamed by her son, Jeffrey, who is an up-and-coming FBI agent. Meanwhile, the Syndicate is continuing their tests to create a vaccine for the Black Cancer and Marita Covarrubias becomes an unwilling test subject.

The Cigarette-Smoking Man returns as Mulder investigates the attempted assassination of a young boy with psychic powers who may be the proof that he has looked for all his life.

Mulder is less than thrilled when an Office of Professional Conduct board refuses to reassign him and Scully to The X-Files and even more so when he learns that Agent Spender and Agent Fowley have become their successors. When Gibson Praise reappears and comes to them for help, Mulder and Scully attempt to continue their quest undercover despite having fewer friends and less access and protection than ever before.

While the Cigarette-Smoking Man recites to an unseen listener everything about the work of the Syndicate involving a global conspiracy in cooperation with an alien species, Cassandra Spender reappears and is pursued by the scientists who would rather kill her than keep her alive. Cassandra runs to Mulder's apartment and demands that he shoot her because she is the culmination of 50 years work - a living alien/human hybrid - and colonization will begin if the aliens find out about her.

The Cigarette-Smoking Man reveals all the government secrets from the past 50 years in order for his son, Jeffery Spender, to join him in his work. Mulder learns that the final stage of the conspiracy will soon begin with the hybridization of the Syndicate members, and he must stop it from happening. Agent Spender deceives his father and arranges for Mulder and Scully to be reassigned to the X-Files, which doesn't sit too well with the Cigarette-Smoking Man.