Grenier's next project was in quite a different vein from his previous work, starring as an edgy activist turned dream date to girl-next-door Nicole (Melissa Joan Hart) in "Drive Me Crazy". He performed well in the film and affected the perfect detached too-cool-to-care facade that teenage girls expect in a heartthrob. For his next role in John Waters' "Cecil B Demented", he portrayed an actor, the leading man in the titular director's latest schlocky offering "Raving Beauty". Grenier returned to hallowed halls, this time as a college student gone wrong in James Toback's "Harvard Man" (2001). Cast opposite Sarah Michelle Gellar, another teen favorite, he played the eponymous basketball star who falls into a life of compulsive gambling and drug abuse.

The actor then took on a series of supporting roles in high-profile projects featuring A-list talent, including Steven Spielberg's "A.I." (2001), opposite Bruce Willis and Colin Farrell in "Hart's War" (2002), and Woody Allen's "Anything Else" (2003), while still snaring leading roles in smaller projects, such as the romantic mystery "Bringing Rain" (2003). But it would be his leading role as movie actor Vincent Chase on the HBO series "Entourage" (2004 - )--loosely based on the antics and exploits of series creator Mark Wahlberg's hangers-on--that would provide Grenier with his most visible vehicle. He was next set to play Anne Hathaway's love interest in the fashion industry tell-all film "The Devil Wears Prada" (lensed 2005) which also starred Meryl Streep.

In addition to his acting career, at the 2002 Tribeca Film Festival, Grenier debuted his documentary "Shot in the Dark" (2002), which chronicles his search for his biological John Dunbar, who was never married and from whom he remains estranged.