Over the course of the next ten years, Huffman alternated between acclaimed stage performances (most often with the Atlantic Theater Company) and television roles. She made her small screen debut as a series regular portraying the government security officer who aids an elderly man who seems to be growing younger in "Stephen King's 'Golden Years'" (CBS, 1991). Guest roles on series like "Law & Order" and "The X-Files" soon followed. Huffman was tapped to play Edward Asner's daughter in the ABC sitcom "Thunder Alley" but was replaced after the pilot. She bounced back from that disappointment with a stage success in Mamet's "The Cryptogram" (1995) and in a supporting turn in the playwright's film "The Spanish Prisoner" (1998) before landing "Sports Night," the Aaron Sorkin-penned sit-com that made her a well-known name.

Her real-life husband Macy—the two were married in 1997—joined the series in its second season, sparking an on-screen partnership that would endure through many projects: they also co-starred in the cable telepic "A Case of Murder" (1999), a comedy-mystery Macy adapted from the Donald Westlake novel; they both appeared in director Paul Thomas Anderson's "Magnolia" (1999); she had an uncredited turn in Macy's award-winning TNT telepic "Door To Door," which he also co-wrote; they reunited in the Showtime mini-series "Out of Order" (2003); and co-starred in the legal potboiler telepic "Reversible Errors" (2004).

After "Sports Night" and away from Macy, Huffman also kept busy solo on the small screen with parts in the telepics "The Heart Department" (2001), "Snap Decision" (2001) and, most impressively, in director John Frankenheimer's acclaimed HBO drama "The Path to War" (2002), playing First Lady “Lady Bird” Johnson. She also scored a pair of high-profile recurring roles, playing Julia Wilcox, Frasier Crane's caustic co-worker and eventual love interest on the hit sit-com "Frasier" from 2003-2004, and Charlotte Ellis in the legal drama "The D.A."

After a stint on the big screen as Kate Hudson's late older sister in the comedy "Raising Helen" (2004), Huffman returned to series drama in the offbeat serial drama "Desperate Housewives" (ABC, 2004 - ), playing Lynette Scavo, a former corporate ladder-climber turned stay-at-home mom who struggles with her insecurities when she can't control her wild children and gets little support from her husband. The show's mega-popularity provided Huffman's career with fresh energy—she scored an Emmy as Outstanding Lead Actress in a Comedy Series for the series' debut season, as well as a 2006 Screen Actors Guild Award for Outstanding Performance by a Female Actor in a Comedy Series—though she continued to remain the most private and low-profile of her co-stars.

Later that same year Huffman had an astonishing turn on the big screen in the indie "Transamerica" (2005) playing a pre-operative transsexual who, on the brink of her transforming surgery, discovered that in her youth she had fathered a son—now a troubled teen hustler on the run. Despite the gender-bending premise, the film followed a traditional road movie dynamic, and Huffman won widespread praise for her nearly unrecognizable, fully formed performance. All the attention she received resulted in a Golden Globe award for Best Performance by an Actress in a Motion Picture – Drama, which almost guaranteed the actress a nomination from the Academy Awards. And she was indeed one of the nominees for Best Actress in a Leading Role when they were announced the morning of January 31, 2006.

While continuing her award-winning stint on “Desperate Housewives,” Huffman returned to the big screen again, playing a San Francisco mother disgruntled with her impulsive, uncontrollable daughter (Lindsay Lohan) in “Georgia Rule” (2007). Angry with her daughter getting into yet another car accident, she sends her to Iowa to live with Georgia (Jane Fonda) her strict, God-fearing grandmother, in order to learn a little down-home discipline—Georgia demands anyone living under her roof to follow all her unbreakable and nonnegotiable rules. While her daughter stands to learn a thing or two, all three women must band together like never before when buried family secrets are unearthed. Despite typically strong performances from Huffman and Honda, and the star power of Lohan, “Georgia Rule” displeased a great many critics with its wavering between ham-fisted comedy and overwrought drama.