Visions of a plane crash bring Frank Black back into service for the FBI. While investigating the crash site Frank meets dedicated young Agent Emma Hollis. Together, they uncover a plot to exterminate sisters who are remote viewers.
Frank and Agent Hollis investigate the deaths of several sisters and their daughters who appear to be genetically engineered "remote viewers". They must find the remaining sisters before the Millennium Group's assassins do.
Emma is investigated by the Internal Affairs when she tries to help her junkie sister who claims that a new designer drug is turning addicts into monsters - literally. She and Frank find evidence of a conspiracy.
On Christmas, Frank and Jordan go on vacation in Vermont. Unexpectedly, they get involved with a supposedly dead Mafia hitman who appears to be living in the woods with two mysterious whimsical healers.
When Jordan falls gravely ill for no apparent reason, Frank likens her condition to the mysterious demise of three people who had previously survived a brush with death. A supernatural stalker appears to be behind it all.
Someone mails Frank (Lance Henriksen) a cassette tape containing seemingly harmless white noise. But Frank links copies of the tape to the bizarre deaths of two people. Also Frank is visited by the ghost of his dead wife.
Frank finds a connection between the murder of a federal prosecutor and his evil archnemesis, Lucy Butler, who now lives with the family of a gubernatorial candidate as the nanny of their little daughter whom she wants for herself.
Frank and Emma investigate the cryptic suicide of Michael Lanyard, an ex-FBI Agent turned member of the Millennium Group, and his final case, the supernatural death of one of the physicists who worked on the Trinity nuclear test in 1945.
An escaped homicidal female psychiatric patient seduces a young patrolman into helping her prove her innocence. Emma believes that a conspiracy may have been behind the woman's imprisonment but Frank is not so sure.
When Frank (Lance Henriksen) receives a series of Polaroid photographs, showing his own death. Frank claims that someone is out to kill him, but authorities suspect he may be having a nervous breakdown.
Frank and Emma examine the disappearance and murders of several young women in Emma's childhood hometown, a small, idyllic, tight-knit community. They try to prove that a local cop did it but the town's sheriff refuses to believe them.
Frank chases a copycat serial killer who somehow perfectly imitates the crimes of the executed serial killer the pursuit of whom almost drove Frank insane. Watts offers to help Emma's ailing father if she joins the Millennium Group.
In the series impromptu finale, Frank, suspecting the Millennium Group's involvement, burns all bridges in his pursuit of the copycat killer. Emma makes her Sophie's choice. The Group betrays Watts. Frank returns in The X-Files: Millennium (1999).