On the small screen, Guest earned an Emmy as one of the writers for "The Lily Tomlin Special" (ABC, 1975), on which he also performed. He then appeared regularly in sketches on the short-lived ABC variety series "Saturday Night with Howard Cosell" (1975) and moved to episodics with an guest appearance on "All in the Family". Proving his dramatic mettle in longforms like "Billion Dollar Bubble" (NBC, 1977) and "It Happened One Christmas" (ABC, 1977), he next delivered a strong portrayal of Watergate felon Jeb Stuart Magruder in the 1979 CBS miniseries "Blind Ambition". Savvy viewers became more aware of Guest when he joined the cast of NBC's "Saturday Night Live" in 1984, serving as the anchor for the "Weekend Update" segment, creating characters like the trainer for a male synchronized swimming pair in a particularly memorable sketch, and impersonating Dr Ruth Westheimer, among others. As the 80s progressed, Guest appeared as a guest on comedy specials featuring "SNL" co-stars Martin Short and Billy Crystal, including the HBO productions "Billy Crystal -- Don't Get Me Started" (1986) and "I, Martin Short, Goes Hollywood" (1989). With the advent of the 1990s. Guest moved behind the camera, co-producing and directing the premiere of the CBS sitcom "Morton and Hayes" and helming the TV-movie remake "Attack of the 50 Ft. Woman" (HBO, 1993), starring Daryl Hannah.

While he enjoyed great critical success in later years for his innovative, largely improvisational documentary-style comedy features, Guest's screen career had an uneven start. He debuted as one of the residents in the Oscar-winning black comedy "The Hospital" (1971) and landed his first romantic lead opposite Melanie Mayron in Claudia Weill's "Girlfriends" (1978). Not until Rob Reiner's spoof of rock documentaries "This Is Spinal Tap" did Guest find his footing. Practically stealing the film with an hilarious turn as the pouty guitarist Nigel Tufnel, the co-writer as well as star of the film entered cult film history along with on and off-screen collaborators Michael McKean and Harry Shearer with this perennial comedy favorite. Reiner later cast the actor as the villainous Count Rugen in "The Princess Bride" (1987) and as a doctor in the military courtroom drama "A Few Good Men" (1992).

Guest moved to the director's chair in 1989 with "The Big Picture" (1989), an insider's look at Hollywood wheeling and dealing filled with good performances and smartly funny jokes. His second effort was "Waiting for Guffman" (1997), in which he cast himself in the central role of a frustrated gay actor unsuccessful in his Off-Broadway pursuits who returns to his home in Missouri to stage a sesquicentennial pageant. Owing a debt to "Spinal Tap", "Guffman" was shot in mock-documentary fashion and affectionately celebrated the American penchant for bad taste. Guest's tour-de-force performance anchored the film, which included incisive bits from Catherine O'Hara, Parker Posey and Fred Willard. His third feature "Almost Heroes" (1998), which followed a bumbling pair of rivals to Lewis and Clark trekking across early 19th-century America, was unfortunately tinged with sadness despite its comic premise as leading actor Chris Farley died before its release. While this stalled at the box office, the 2000 follow-up "Best in Show" proved a critical success and a niche market hit. A sharp and clever comedy set at a dog show, the film followed Guest's successful improvised mockumentary pattern, and reteamed Willard, O'Hara and Posey as well as "SCTV" veteran Eugene Levy, who co-wrote the thematic screenplay outline with Guest. Expecting the most from his players and getting it, "Best in Show" proved even more consistently funny than the riotous "Guffman". From O'Hara and Levy's happily mismatched couple to Willard's alarmingly off-the-cuff announcer, the film celebrated rather than trounced upon its characters quirks. with the same warm sense of humor present in his prior work. Fondly remembering the explosion of folk music in his New York neighborhood, Guest summoned Eugene Levy as the two began to work on their next project. The result came in the form of the musical comedy "A Mighty Wind" (2003), a feature about a group of folk music have-been's who decides to get together one last time to memorialize a deceased concert promoter.