Born Apr. 18, 1963 in the Boston suburb of Brookline, MA, O’Brien was the third child of six in his Irish-American family. The son of Dr. Thomas O’Brien, a research physician and associate professor at Harvard Medical School, and Ruth Reardon O’Brien, a former lawyer, young O’Brien graduated as valedictorian from Brookline High School and went on to attend Harvard University. As an undergrad at the prestigious university, he wrote for the school’s legendary humor magazine, The Harvard Lampoon, of which he also served as president during his sophomore and junior years. In 1985, O’Brien graduated magna cum laude with a bachelor’s degree in American History and Literature.

After graduating Harvard, O’Brien moved to Los Angeles, where he joined the writing staff of the HBO series, “Not Necessarily the News” (1983-86), for which he wrote regularly for two years. While on the series, O’Brien also found time to act in improvisational skits, most notably for the Los Angeles-based comedy troupe, The Groundlings. In 1988, O’Brien’s comedic writing talents caught the eye of “Saturday Night Live” (NBC, 1975- ) executive producer Lorne Michaels, and he was soon hired on as a writer for the infamous late-night comedy show. O’Brien wrote three-and-a-half years worth of “SNL” sketches, penning the popular recurring bits, “Mr. Short-Term Memory,” “The Girl Watchers” and sketches featuring Dieter, the androgynous West German talk show host played by Mike Myers. His most notorious "SNL" moment was writing the now infamous nude beach skit where "penis" was uttered 60 times. His efforts paid off when he and his fellow “SNL” writers shared an Emmy Award in 1989 for Outstanding Writing in a Comedy or Variety Series.

O’Brien left “SNL” in 1991 to write and produce the somewhat infamous television pilot that never was, “Lookwell” (NBC, 1991), which starred Adam West as a former star of a cancelled TV cop show who continued to try to solve crimes. The pilot aired that July but was not picked up as a series. Later that year, O’Brien was hired on as a writer and producer for the Fox animated series, “The Simpsons” (FOX, 1989- ). So impressive were his talents, he was soon promoted to supervising producer and worked on the series for two years. During those years, O’Brien penned what many believe to be the best "Simpsons" episode of all time – certainly, it was O’Brien’s favorite – “Marge vs. The Monorail.” The 1993 fourth-season classic was a song-filled take-off on “The Music Man” and featured the guest voices of Phil Hartman as a fast-talking monorail salesman and Leonard Nimoy as a stuffy, enigmatic version of himself.

Around this same time, another opportunity was presented, one that eclipsed O'Brien's success on both “SNL” and “The Simpsons.” In April, 1993, he seemingly came out of nowhere to win the coveted hosting slot as David Letterman’s successor on NBC’s “Late Night with…” (NBC, 1982- ). Comic Andy Richter was hired on as O’Brien’s sidekick and Bruce Springsteen drummer, Max Weinberg, was brought on as the show’s new Paul Schaffer-esque music director. Though the series first received poor ratings and rumors of cancellation rumbled through the halls of 30 Rockefeller Plaza, O’Brien’s wacky and self-deprecating style of comedy eventually caught on. Dubbed “Late Night’s King of Cool” by Entertainment Weekly, O’Brien and staff delivered with sketches like “The Masturbating Bear,” “In the Year 2000,” and “Pimpbot 5000” – to say nothing of introducing the world to Triumph the Insult Comic Dog. Over the years, O’Brien and the “Late Night” writing team consistently garnered Emmy and Writer’s Guild Award nominations for Outstanding Writing in a Comedy or Variety Series, including two consecutive WGA wins in 2002 and 2003.

With his success in late-night TV, O’Brien formed his own production company, Conaco, in 2001 which shared productions credits on “Late Night.” During his “Late Night” run, O’Brien also appeared as a guest on the series “The Single Guy” (NBC, 1995-97), “Spin City” (ABC, 1996-2002), and “Andy Richter Controls the Universe” (FOX, 2002-04). In 2002, host O’Brien delivered what many considered the Emmy Award’s funniest opening monologue in its televised history. Due to his continued critical success and devoted late night fan base, it was announced to much fanfare in 2004 that the now iconic redhead would take over for Jay Leno as host of NBC’s “The Tonight Show” (1992- ) upon Leno’s retirement from the show in 2009. In late 2007, NBC-Universal President and CEO Jeff Zucker confirmed the network’s commitment to O’Brien after rumors of Leno perhaps having second thoughts about leaving “The Tonight Show.” At the same time O'Brien was relishing NBC's continued committment to him and his gang of merrymakers headquarted at 30 Rock, the comic found himself on the receiving end of a stalking incident, involving of all things, a Catholic priest obsessed by him. The threats, which were publically leaked, were considered serious enough that the police got involved to ensure his safety.