With the X-Files closed, Scully has been assigned as an instructor at the FBI Academy while Mulder is doing menial surveillance work. After meeting with Senator Matheson, one of his supporters in regards to the X-Files, Mulder disobeys orders and heads to an abandoned SETI site in Puerto Rico which has inexplicably reactivated itself and could provide proof of contact with extra-terrestrial life.

An investigation into a video of an alien autopsy puts Mulder and Scully in the middle of a conspiracy involving WWII Japanese scientists brought to America to continue their experiments which may shed light on Scully's abduction.

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.