Over the next few years, Harris quickly racked up a number of television credits, including appearances in the TV-movies "Too Good to Be True" (NBC, 1988) "Home Fires Burning" (CBS, 1989), "Cold Sassy Tree" (TNT, 1989) and a starring guest role in "Blues for Buder" (ABC, 1989), one of the series of "B.L. Stryker" detective TV movies, starring Burt Reynolds. That same year he landed the role of the pubescent "Doogie Howser, M.D.,” likeably playing the sixteen-year-old medical school graduate, dealing with his patients and parents as he struggled through his residency and adolescence simultaneously. To many viewers, Harris became inextricable from the role, and his skillful, award-winning performance as the young idealistic medical professional threatened to limit his future career prospects upon the series' 1992 demise.

While on "Doogie Howser, M.D." and immediately following, Harris kept busy with a spate of television appearances in longforms and series guest roles. The year 1991 alone saw him take parts on "Blossom" (NBC), "Carol & Company" (CBS) and "The Simpsons" (Fox). The voice work of the latter prepared him for a regular starring role on the short-lived politically themed ABC prime-time animated series "Capitol Critters" (1992), playing Max, a country mouse who ends up in Washington, D.C. Featured guest parts on "Quantum Leap" (NBC) and "Murder, She Wrote" (CBS) also came in 1992, before he took on a series of characters in fact-based TV movies, most notably in the true crime NBC production "A Family Torn Apart" and CBS' "Snowbound: The Jim and Jennifer Stolpa Story", playing a man who, along with his wife and five-month-old child, survives after days trapped in a Nevada avalanche. He could additionally be seen in the 1995 telepics "Not Our Son" (CBS), "My Antonia" (USA Network), "The Man in the Attic" (Showtime) and "Legacy of Sin: The William Coit Story" (Fox).

After time away from television to pursue stage roles and feature work, Harris returned with a starring turn as a young successful businessman on a journey to self-discovery in the 1998 CBS holiday offering "The Christmas Wish" and took a supporting role the following year as King Charles VII opposite Leelee Sobieski's "Joan of Arc" (also CBS). He returned to regular series work in NBC's "Stark Raving Mad" in 1999, starring as the neurotic, germ-phobic editor of a zany horror novelist (Tony Shalhoub). The series' plum time slot (nestled between heavy hitters "Frasier" and "ER") and highly capable, watchable performances by Harris and Shalhoub helped to propel this otherwise by-the-numbers sitcom.

After a nine-year absence from features, Harris returned to the big screen with a supporting role in Paul Verhoeven's sci-fi actioner "Starship Troopers" (1997) and could be seen that same year alongside Matthew Lillard in the independent drama "The Animal Room.” 1998 saw him take on the role of a Harvard Law student who gets emotionally involved after being hired to sire the child of a successful, infertile couple (Madeline Stowe and William Hurt) in the 1930s-set drama "The Proposition" (1998). He would follow up these little-seen roles with a turn in "The Next Best Thing" (lensed 1999), starring Madonna and Rupert Everett respectively as a woman and her gay male friend who decide to have a child together, with dramatic repercussions.

While the small screen afforded Harris fame and a comfortable lifestyle, the actor had been interested in pursuing stage work from the beginnings of his career. He made his debut at the La Jolla Playhouse in 1993, portraying a young man who runs across unimaginable hardships in pursuit of the American dream in "Luck, Pluck and Virtue,” James Lapine's satirical take on the Horatio Alger success story. This role showcased Harris' potential as a charismatic stage player with a talent for physical comedy. In 1997, he was cast in "Rent,” originating the role of Mark, the bleached blonde aspiring filmmaker and the piece's narrator, on the Los Angeles stage. Harris received positive reviews for his performance, his strong singing voice and deft moves proving him a surprisingly gifted musical theater player. He followed up playing Romeo to Emily Bergl's Juliet in a 1998 Old Globe Theater production of the Shakespeare classic, before being touted by critics as a highlight of a 1999 Los Angeles concert version of the Sondheim musical "Sweeney Todd,” appearing in the star-studded cast alongside Kelsey Grammer and Christine Baranski.

Returning to the small screen in 1999, Harris teamed up with future “Monk” star Emmy-winner Tony Shalhoub in the short-lived sitcom Stark Raving Mad (NBC, 1999-2000). Despite winning a People's Choice Award for Favorite New Television Comedy Series in 2000, the low-rated “Stark Raving Mad” got the ax from NBC after just 22 episodes. Not one to waste time, Harris simply returned to the stage and embarked on a highly successful run on Broadway performing in such A-list productions as 2001’s “Proof” (opposite Anne Heche) and 2003’s revival of “Cabaret,” (alongside Deborah Gibson and Tom Bosley.) Drawing critical acclaim for his performance as the Emcee in “Cabaret” (a role originally made famous by Joel Grey,) Harris was tapped next to play the role of Lee Harvey Oswald in Stephen Sondheim's controversial musical, “Assassins.”

Taking another break from the stage in 2005, Harris landed a co-starring role as serial womanizer Barney Stinson on the hugely popular ensemble sitcom “How I Met Your Mother” (CBS, 2005- ). An instant hit in the ratings, “How I Met Your Mother” was renewed for a second season in May 2006. Unfortunately, as the show’s popularity increased, so too did the public’s interest in the personal lives of its stars. Harris, in particular, became a target of rampant gossip after it was rumored at the start of “How I Met…”’s 2nd season that he was secretly a closeted homosexual. After an initial denial from his publicist, Harris personally ended the mounting speculation about his sexuality by issuing a statement to People magazine's website in November 2006, in which he confirmed the rumors: "Because of speculation and interest in my private life and relationships… [I] am quite proud to say that I am a very content gay man living my life to the fullest." While a few Hollywood insiders wondered if Harris’ admission might hurt his career; in reality, the exact opposite appeared to be the case. Not only did ratings for “How I Met Your Mother” remain solid into its third season, Harris also received his first Emmy nomination for Outstanding Supporting Actor in a Comedy Series on July 19, 2007.