FBI special agent Fox Mulder handles the "X-files", unsolved cases classified as impossible to crack, inexplicable by any other than paranormal means. If Mulder weren’t so determined to get to the bottom of them, and in such unconventional ways, they would be long forgotten. Which is just the idea behind assigning Mulder a new assistant, Dana Scully, a physician and scientist whose expertise, her superiors hope, will discredit Mulder’s bizarre ideas for one and for all. Instead, as time goes by, Scully herself is shaken by events that challenge her convictions and her firm belief in an "official science".

Their first case together involves a series of deaths and disappearances of students at the local high school in Bellefleur, Oregon. The events appear to be connected; Mulder believes that the individuals have been abducted by aliens. Scully’s initial skepticism wavers in the face of a body of evidence that, however, is mostly destroyed in a fire.

The pilot episode contains the seeds of what will become the recurring themes and key characters of what has been dubbed the X-Files "mythology". The red marks and the Smoking Man are part of the narrative thread that runs through the entire series: an alien invasion and the conspiracy of a "deviated" group that has infiltrated the government to cover up all traces of the event.