Mulder vindt in zijn krant een audiocassette. Op de tape heeft iemand een tekst ingesproken: een wetenschapper werd gedood door vuur ondanks er geen enkel bewijs of aanwijzing is dat het lichaam brandwonden heeft. Scully wordt tijdelijk vervangen door Krycek.

Voormalig FBI-agent Duane Barry ontsnapt uit een psychiatrische instelling. Nu houdt hij enkele mensen gegijzeld in een reisbureau. Mulder en Krycek worden ter plaatse gestuurd voor de onderhandelingen, zeker omdat de man beweert ooit te zijn ontvoerd door een ufo.

Mulder vindt op zijn antwoordapparaat een bericht van Scully met de melding dat ze wordt aangevallen. Mulder is er zeker van dat Duane Barry de dader is en haast zich naar het huis van Scully. Duane heeft Scully ontvoerd en wil haar opofferen voor de buitenaardse wezens.

Via "The Lone Gunmen" komt Mulder in contact met een hacker die uiterst geheime staatsinformatie heeft kunnen downloaden. De bestanden zijn geëncrypteerd in de Navajo-indianentaal en kunnen enkel ontcijferd worden door een hacker die dergelijke taal spreekt. Zo komen ze in contact met Cigarette Smoking Man.

Scully finds her career with the FBI in jeopardy as Mulder is still missing and the Cigarette Smoking Man is pursuing the stolen files. The Navajo elders find Mulder's body in a cave and perform an ancient ceremony to call the spirit back to the empty vessel.

A.D. Skinner and Scully are at a standoff when Mulder bursts in and discovers that Skinner has the digital tape. Reunited, Mulder and Scully travel to a secret vault inside a mine and find an elaborate filing system of medical records which reveals that Mulder's sister may not have been the first choice for abduction. Meanwhile, Skinner deals with the Cigarette-Smoking Man for their safety.

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.

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.

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 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.

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.

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.

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 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.

After not knowing Fox Mulder's whereabouts for the last year, A.D. Skinner and Agent Scully learn he's being held for the murder of a military man he couldn't possibly have killed: Knowle Rohrer, one of the government's secret super-soldiers. With Skinner acting as Mulder's defense, people who Mulder has dealt with during his last nine years as an FBI agent testify on his behalf. But the military tribunal isn't interested in the truth.