The X-Files is a television series that aired from 1993 to 2002. The premise follows agents of the FBI who investigate cases of the paranormal or supernatural. The popular series spawned two theatrical films, comic books, video games and other media and merchandise, with the characters of Scully & Mulder showing up as number thirty two on Bravo's list of the 100 Greatest TV Characters.
- The Muppets Tonight pilot featured a brief spoof on the name of the series in Gonzo's line-up of KMUP programming: "X-Flies" was scheduled to air at 9:00 on Fridays.
- The structure of Sesame Street Episode 3833 follows an X-Files theme as Telly follows the mystery of a strange-looking X, about which no one else will believe in. Telly's X-sightings are scored by a xylophone playing a variation on Mark Snow's X-Files theme. In a fit of frustration, Telly shouts the tagline from the series, "The truth is out there!"
- A sketch titled "Baby Talk" features Baby Natasha hosting her own talk show with an all baby band. The announcer (Jerry Nelson) announces Natasha's guest as the star of The X-Files, the letter X. The baby band underscores his entrance with music that parodies Mark Snow's theme from the TV series.
- In Miss Piggy's Rules, Miss Piggy suggests calling your ex-boyfriend's house repeatedly whenever X-Files is on as a way of getting even after a breakup.
- In the season three episode "Revelations", Mulder and Scully walk down an elementary school corridor past a wall mural of Ernie and Bert.
- In the season four episode "Max", Mulder describes an item under x-ray over the phone with Scully, "More people are trying to get their hands on this thing than a Tickle Me Elmo doll." The episode aired a few months after the holiday shopping season where the dolls were consistently sold out in stores.
- Gillian Anderson played main character Special Agent Dana Scully
- Edward Asner played Maurice in "How the Ghosts Stole Christmas" (1998)
- Richard Belzer played Det. John Munch in "Unusual Suspects" (1997)
- Jack Black played Bart 'Zero' Liquori in " D.P.O."
- Peter Boyle played Clyde Bruckman in "Clyde Bruckman's Final Repose"
- Billy Connolly plays a main character in The X-Files: I Want to Believe (2008)
- Juliana Donald played Nancy Kline in "Arcadia"
- Seth Green played Emil in "Deep Throat" (1993)
- David Alan Grier was uncredited for an audience member in "Hollywood A.D." (2000)
- Lillian Hurst played Flakita in "El Mundo Gira"
- Martin Landau played Alvin Kurtzweil in The X-Files: Fight the Future (1998)
- Michael McKean played Morris Fletcher in 4 episodes (1998-2002)
- Jody St. Michael played Sophie in "Fearful Symmetry"
- Ryan Reynolds played Jay De Boom in "Syzygy" (1996)
- Deep Roy played Beggar Man in "Badlaa"
- Tony Shalhoub played Dr. Chester Ray Banton in "Soft Light" (1995)
- Allison Smith played Patti in "Trust No 1"
- Jerry Springer played himself in "The Post-Modern Prometheus" (1997)
- Nick Tate played Eugene Openshaw in "Two Fathers"
- Lily Tomlin played Lydia in "How the Ghosts Stole Christmas" (1998)
- Alex Trebek played himself in "Jose Chung's From Outer Space" (1996)
- Danny Trejo played Spider-Man / Cesar Ocampo in "Redrum" (2000)
- Lisa Waltz played Lauren Kyte in "Shadows" (1993)
- Fritz Weaver played Albert Sorenson in "Tunguska" and "Terma"
- Frank Welker provided Special Vocal Effects and Animal Voices for "Fearful Symmetry" (1995) and "Teso dos Bichos" (1996)
- David Wohl played Kenneth Ungar in "Kaddish"
- B. D. Wong played Det. Glen Chao in "Hell Money" (1996)