In 1997, Vartan gave a breakthrough performance in "The Myth of Fingerprints", starring as a sweet but unambitious son returning to the family home for Thanksgiving along with his brother, two sisters and girlfriend Margaret (Hope Davis). His Jake was a particularly effective contrast to his forthright girlfriend, his ill-tempered sister Mia (Julianne Moore) and his troubled brother Warren (Noah Wyle). Next up was "Touch Me" (1998), in which he appeared as a lecherous but charming health club manager who gets involved with an aerobics instructor (Amanda Peet) in this AIDS-themed drama. He could also be seen in "The Curve/Dead Man's Curve", a college-set black comedy given a limited regional release before landing on video shelves. Vartan starred as an undergraduate whose desperation to enter the Harvard Business School leads him to find ways besides studying to get straight As. He and roommate Tim (a particularly sinister Matthew Lillard) scheme to murder their third roommate (a distasteful character played by Randall Batinkoff) and make the death appear self-afflicted, following the urban legend that roommates of a suicide victim get an automatic 4.0 GPA as condolence. Vartan's characterization was most interesting, making the role sympathetic despite murderous intentions and blind ambition.

1999 would see the actor come to the forefront as a leading man with starring roles in two films. In the romantic comedy "Never Been Kissed", he was cast as a young teacher lovestruck by an undercover reporter posing as a student (Drew Barrymore) while the indie "It Had to Be You" teamed him with Natasha Henstridge in a tale of a couple who discover a mutual attraction while planning their respective weddings. In 2000 he had a supporting turn in the dismal Madonna-Rupert Everett comedy "The Next Best Thing," and took the leading role in the drama "Sand," as a man whose life is upended by the arrival of his troublemaking family.

Despite the regular flow of feature film work, television would prove to be the medium that would elevate Vartan from actor to star. His early TV work included "Murder, Obliquely", a 1993 segment of the Showtime series "Fallen Angels" and he made a memorable guest appearance as the handsome son of Courtney Cox's much older boyfriend (Tom Selleck) on a 1997 episode of NBC's "Friends" before landing a two-episode love interest stint on "Ally McBeal" in 2000. He had a high-profile turn as the legendary knight Lancelot opposite Anjelica Huston, Joan Allen and Julianna Margulies in the acclaimed CBS miniseries "The Mists of Avalon" in 2001, the same year he was cast in his breaktrhough as Agent Michael Vaughn, the tortured love interest of college-girl-turned-spy Sydney Bristow (Jennifer Garner) on the adventure series "Alias" (ABC, 2001 - ). His "Alias" stint also landed him in the entertainment magazines when he was briefly romantically linked to his co-star Garner immediately following the breakup of her marriage to actor Scott Foley. His character was killed off in 2005, after rumors of Vaughn's impending demise prompted rabid fans to protest his departure.

Vartan's increased profile as a result of his "Alias" role led to more work in features: in the creepy indie drama "One Hour Photo" (2002) he was the husband and father in a family that soon becomes the obessession of a distrubed photo processor played by Robin Williams. Next was a role in the romantic comedy "Monster-In-Law" (2005) as Jennifer Lopez's perfect man whose domineering mother (Jane Fonda) tried to destroy the couple's relationship.