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.

Mulder and Scully have 24 hours to save A.D. Skinner from being killed by a biologically engineered disease. The disease appears to be created by a shadowy government organization, but in order to save Skinner's life they must determine who wants him dead and why. With Skinner's condition worsening, Mulder seeks assistance from Senator Matheson, who he hopes can provide some answers and help him to find a cure.

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.

Two scientists confer about each of their metal objects that were found in Africa and they theorize that the objects are pieces of a puzzle which could be undeniable proof that human, plant, and animal life did not originate on this planet. When one of the scientists is killed and the objects are stolen, the agents investigate and Mulder begins to experience severe neurological pain caused by the objects.

While Scully travels to Africa to piece together the meaning of the symbols on the spaceship beached on the Ivory Coast, Mulder is imprisoned by his own frenetic brain activity. He manages to get a message to Skinner who finds Kritschgau, and together they try to understand what is happening to Mulder before it is too late.

Scully frantically searches for a way to help her ailing partner without having anyone to turn to for help, while a catatonic Mulder's dreams lead him away from his mission and the X-Files to a place which he believes is a better life.

A young girl inexplicably disappears from her home, and Mulder requests the case even though it is a full FBI matter, not just an X-File. When Mulder takes some outrageous leaps to convince the girl's parents that she will be found, Scully fears that Mulder is becoming too personally involved with the case because of his sister's abduction.

After arresting the murderer of Amber-Lynn LaPierre and discovering a mass grave site containing the bodies of dozens of missing children, a man comes to Mulder and claims to have had visions of other victims who aren't buried at the site. Despite Scully's objections, he takes Mulder on a journey which reveals what truly happened to his sister.

The Cigarette-Smoking Man offers to show Scully the cure for all diseases if she travels with him, but on one condition: Mulder must not know about her trip.

Mulder and Scully return to the town of their first X-Files investigation where a UFO has crashed in the forest. The Cigarette-Smoking Man arranges for Krycek to be released from prison in order for him to make contact with the aliens and begin rebuilding the "Project", while Scully's health appears to be taking a turn.

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.