After appearing in several plays (such as Rosencrantz & Guildenstern Are Dead and The Bald Soprano)[citation needed], she moved to Los Angeles, California and in 1987 got her first break in a role in Walt Disney's made-for-TV film Student Exchange. Tierney's first starring role in a film was in a low-budget, independently-produced film called Dead Women in Lingerie, shot in 24 days. Although the cast included well-known actors such as Jerry Orbach as her boss, and June Lockhart and Lyle Waggoner as her parents, the film, a thriller with opening and closing credits paying tribute to the plights of Illegal immigrants post-1986, never received a theatrical release. Much later (in 2005), the film was released on DVD by MTI Home Video; the company's press release and packaging makes it clear that the release is an attempt to capitalize on her more recent career successes.

Tierney continued winning small roles in film and television, though it was not until her leading role in NewsRadio from 1995-1999 and roles in major feature films such as Liar Liar, Primary Colors, and Forces of Nature that she received regular national exposure.

It was after NewsRadio ended that she got her role on ER. She started off guest starring as an OB nurse, a role which expanded in 2000 to a full-time regular part as an ER nurse; within a year, her work on ER had earned her an Emmy Award nomination, recognition she credits to a "juicy" story arc featuring her and Sally Field.[1]. Tierney's character Abby Lockhart graduated from medical school and became a Doctor at the end of the 2003-2004 season.

She starred in Scotland, Pa., playing a Lady Macbeth-like role written specifically for her by writer/director and then-husband Billy Morrissette. She also collaborated with NewsRadio writer Joe Furey for a special "Working with Joe Furey" featurette for Furey's film Love and Support.

Tierney won the second season tournament of Bravo's Celebrity Poker Showdown against Lauren Graham, her former NewsRadio colleague. The show, first telecast in 2004, was hosted by Dave Foley, who was her co-lead and romantic interest in NewsRadio.