The following fall, Messing landed what became her breakthrough role, interior designer Grace Adler whose best friend is openly gay lawyer Will Truman in the hit NBC sitcom "Will & Grace" (NBC, 1998 - ). During the series' first season, the comedy struggled a bit, with mixed to positive reaction from critics and audiences (particularly gay and lesbian viewers). By the show's second season, though, the ensemble had clicked and Messing's well-timed reactions to her co-stars Eric McCormack, Sean Hayes and Megan Mullally, were among the pleasures for viewers.

While fairly busy with the series' schedule, she found time to accept the challenging role of Mary Magdalene in CBS' biblical miniseries "Jesus" (2000) and supporting roles in the Woody Allen comedy "Happy Endings" and "The Mothman Prophecies" (both 2002). In 2003, after being nominated for an Emmy four times for her portrayal of Grace Adler, Messing was finally rewarded with her first trophy as best lead actress in a comedy. In 2004 she returned to the big screen in a small but appealing supporting role in "Along Came Polly" as Ben Stiller's unfaithful new bride; she voiced the comic strip she-cat Arlene in live action/CGI adaptation of the comic strip "Garfield"; and her real-life pregnancy was humorously not written into the plotlines of "Will & Grace"--instead of hiding behind props and counters, the usually willowy actress continued to appear with her swelling, bedraped frame largely unexplained until doctor-ordered bedrest forced her out of the season's final episode. After returning to the series, it was on to a full-fledged leading role in the romantic comedy "The Wedding Date" (2005), playing a woman who hires a man to pose as her new boyfriend at a family wedding and discovers herself falling in love with her escort (Dermot Mulroney).