In Washington, D.C., Agent Fox Mulder appears before an FBI panel regarding his experiences in Antarctica. Assistant Director Walter Skinner (Mitch Pileggi) tells Mulder that he and Scully have been denied reassignment to the division. Mulder goes to his former basement office, only to discover that Jeffrey Spender (Chris Owens) and Diana Fowley (Mimi Rogers) have been assigned to the X-Files. Going against orders, Mulder and Scully track down an escaped alien in Phoenix, Arizona while Cigarette Smoking Man (William B. Davis) gives chase. Mulder and Scully eventually discover that Cigarette Smoking Man has been using Gibson Praise to locate the creature. Scully brings Gibson to the hospital, where it is determined that he has the alien virus in his blood.[1] Later, Skinner is mysteriously poisoned by a nanorobot infection. The culprit is revealed to be Alex Krycek (Nicholas Lea), a rogue FBI agent who formerly worked for the Syndicate, who continues to control the potentially debilitating nanotechnology in Skinner's system in order to achieve his goals. 
Mulder and Scully later learn of reports of rebel aliens burning doctors who were working on Cassandra Spender (Veronica Cartwright), an alien abductee and mother of Jeffrey Spender. Skinner takes Spender to the scene, where Cassandra asks for Mulder. She informs Mulder and Scully that the aliens are here to destroy all life on Earth. She claims that a rebel force of aliens are mutilating their faces to prevent infection by the black oil. Cigarette Smoking Man reveals everything to Diana Fowley, who agrees to help him and betray Mulder. Cassandra later escapes from a hospital and arrives at Mulder's apartment, demanding that he shoot her because she is the embodiment of fifty years of work by the Syndicate—an alien-human hybrid that will trigger colonization if the aliens learn of her existence. 
Fowley arrives and forcibly takes Mulder, Cassandra, and Scully to a CDC facility at Fort Marlene. There, Mulder runs into Marita Covarrubias (Laurie Holden). Marita tells Mulder that she was subjected to Syndicate-run black oil vaccine tests. Meanwhile, the Syndicate rendezvous at a checkpoint, preparing to be taken away by the Colonists, who are prepping for invasion. However, they are met by the alien rebels, who incinerate them all, including Cassandra; Cigarette Smoking Man and Fowley escape. Jeffrey Spender is then purportedly killed by Cigarette Smoking Man. 
Several months later, a metallic artifact with inscriptions is discovered on the beach of Côte d'Ivoire in Africa. After Mulder examines rubbings of the object, he begins suffering from a headache, seemingly caused by the rubbings. Mulder's condition worsens, but he gains telepathic abilities. Chuck Burks (Bill Dow) tells them that the symbols on the artifact are Navajo. Eventually, Mulder passes into an aggravated delusional state and is placed under observation at a hospital. Hoping to find an answer, Scully rushes to Côte d'Ivoire and finds the massive wreck of a large spacecraft partially buried in the beach.