The show centers on FBI special agents Fox Mulder (Duchovny) and Dana Scully (Gillian Anderson) who work on cases linked to the paranormal, called X-Files.

In this episode, Mulder and Scully investigate the murders of human clones working in abortion clinics at the hands of a shapeshifting assassin (Thompson).

As Mulder is lowered into a tub of water, Dana Scully bursts in and tells the doctors that the cold is the only thing keeping him alive.

Two weeks earlier, in the Beaufort Sea, crewmen on a ship spot a light in the sky that soon crashes into the water.

Two days later, the Bounty Hunter arrives at an abortion clinic in Scranton, Pennsylvania, and kills a doctor by stabbing him in the back of the neck with a stiletto weapon, then sets the building on fire and escapes.

After interviewing a pro-life priest who had threatened one of the doctors, they are able to use a newspaper advertisement looking for one of the men to track another one, Aaron Baker, to Syracuse, New York.

After Walter Skinner hears of Weiss' death and closes the case, the agents meet CIA official Ambrose Chapel, who tells them that the doctors are clones from a Soviet genetics program and are being systematically killed by both the Russian and U.S. governments.

Scully finds an address on a bag recovered from Dickens' residence and heads there, discovering a lab that is in the process of being destroyed by "Chapel."

"[2] Actor Darren McGavin, star of Kolchak: The Night Stalker, was originally sought to play the role of Bill Mulder, but was unable due to his work schedule.

[2] Carter said that while "Colony" was a "crystallization of the series' mythology", it "came about inadvertently", following David Duchovny's suggestion to face an alien bounty hunter.

[4] The alien weapon, described by the cast and crew as "the ice pick", was done with an air hose that ran through Brian Thompson's arm.

[11] Michelle Bush, in her book Myth-X, wrote that "Colony" presents a moral dilemma for the characters, noting that "on the surface Mulder's quest appears righteous, however, the results of his quest would suggest otherwise", and adding "generally the ideology that focuses on a single life's (be that human or alien) importance is successful, whereas Mulder's ideology of finding the truth at all costs is not".

[12] Duchovny's portrayal of Fox Mulder in this episode has been cited as an example of the character's reversal of traditional gender roles—his openness and vulnerability when confronted with what he believes is his prodigal sister casts him "in a pattern typically engendered as female.