During that time he also briefly appeared as one half of the comedy team of Stack and Lane, until he was cast in the 1982 Broadway revival of Noël Coward's Present Laughter directed by and starring George C. Scott.

That led to an extensive career onstage, where he had a long friendship and fruitful collaboration with the playwright Terrence McNally which started in 1989 with the Manhattan Theater Club production of The Lisbon Traviata.

Among his 25 Broadway credits are The Man Who Came To Dinner (2000), The Odd Couple (2005), Butley (2006), Waiting for Godot (2009), The Addams Family (2010), It's Only a Play (2014), Gary: A Sequel to Titus Andronicus (2019), and Pictures from Home (2023).

[citation needed] He made his Broadway debut in a 1982 revival of Noël Coward's Present Laughter as Roland Maule (Drama Desk nomination) with George C. Scott, Kate Burton, Dana Ivey, Bette Henritze, Elizabeth Hubbard, Jim Piddock, and Christine Lahti.

[22] In 1992, he starred in the hit revival of Guys and Dolls, playing Nathan Detroit, the character who lent him his name, opposite Peter Gallagher and Faith Prince.

[27] His professional association with his close friend the playwright Terrence McNally, whom he met in 1987,[28] includes roles in The Lisbon Traviata (Drama Desk and Lucille Lortel Awards, and Outer Critics Circle nomination),[29][30] Bad Habits, Lips Together, Teeth Apart, Love!

[40] The film, an American remake of the classic French farce La Cage aux Folles, was directed by Mike Nichols with a screenplay by Elaine May, and starred Robin Williams, Lane, and Gene Hackman, and went on to be a big success.

[42] His collaboration with Sondheim would continue when Lane revised the original book for and starred in the Broadway debut of the composer's The Frogs at Lincoln Center in 2004.

[43] Lane appeared in the 1997 dark comedy Mouse Hunt, one of the first films to come out of the newly formed DreamWorks Studios, in which he co-starred with British comedian Lee Evans and Christopher Walken.

He acted in the comedy Isn't She Great (2000) opposite Bette Midler, the crime drama Trixie (2000), and voiced a character in the animated science fiction film Titan A.E.

He then appeared as Vincent Crummles in a film adaptation of Nicholas Nickleby (2002) and the cast received the Ensemble Acting award from the National Board of Review.

[57] In 2004, Lane revised the libretto and portrayed Dionysus in the revival of Stephen Sondheim's musical The Frogs which opened at the Vivian Beaumont Theater at Lincoln Center on Broadway.

[59] His performance in the film version, opposite Broadway co-star Matthew Broderick as Leo Bloom, earned him his second nomination for the Golden Globe Award for Best Actor – Motion Picture Musical or Comedy.

In 2009, Lane starred in the musical version of The Addams Family as Gomez in Chicago, a role he reprised on Broadway the following year, receiving Drama Desk and Outer Critics Circle nominations.

[14] Receiving rave reviews,[71][72] it won six Jeff Awards, including Best Ensemble, director, and Production,[73] and is the most successful play to date in the theater's history.

[74] From 2010 to 2019, Lane portrayed Pepper Saltzman in the ABC sitcom Modern Family for which he received three Primetime Emmy Award for Outstanding Guest Actor in a Comedy Series nominations.

In the spring of 2013, Lane returned to Broadway in The Nance, a Lincoln Center production of a new play by Douglas Carter Beane that was directed by Jack O'Brien.

[78] In autumn 2014, he appeared in an all-star ensemble of Terrence McNally's revised and updated It's Only a Play, with F. Murray Abraham, Matthew Broderick, Stockard Channing, Rupert Grint, Megan Mullally, and Micah Stock.

New York Post film critic Elizabeth Vincentelli wrote of his performance, "Lane, one of his generation's most brilliant comic actors...[hits] the sweet spot between pretend perkiness and self-loathing".

[86] In fall of 2016, he returned to Broadway to rave reviews in an all-star revival of Hecht and MacArthur's The Front Page, directed by Jack O'Brien and produced by Scott Rudin.

Lane reprised his acclaimed portrayal on Broadway at the Neil Simon Theatre, and won the Tony, Drama Desk, and Outer Critics Circle Awards for Best Featured Actor in a Play.

In March 2019, Lane starred in Taylor Mac's absurdist black comedy Gary: A Sequel to Titus Andronicus at the Booth Theatre directed by George C. Wolfe.

[89] Lane played the role of Lewis Michener on Showtime's Penny Dreadful: City of Angels which premiered April 26, 2020, and ran for one season.

Lane portrayed the father and former razor blade salesman to his son a photographer, played by Danny Burstein, who's remembering his visits with his family.

"[93] Also in 2023, Lane co-starred in Ari Aster's new A24 film, Beau Is Afraid alongside Joaquin Phoenix, Amy Ryan, and Patti LuPone.

[98] He was part of the voice cast for Spellbound, a new animated film from Skydance for Netflix, with Rachel Zegler, Nicole Kidman, Javier Bardem, Jenifer Lewis and John Lithgow, as well as the Ryan Murphy miniseries, Monsters: The Lyle and Erik Menendez Story, as Dominick Dunne.

[99] He is starring in a new Hulu multi-cam comedy, Mid-Century Modern, again produced by Ryan Murphy, created by Max Mutchnick and David Kohan who are the creators of Will and Grace, and co-starring Matt Bomer, Linda Lavin, and Nathan Lee Graham.

His roles in theatre range from musical comedies, Guys and Dolls (1992), A Funny Thing Happened on the Way to the Forum (1996), The Producers (2001) and The Addams Family (2010) to dramatic roles in the work of Terrence McNally, Jon Robin Baitz, and Simon Gray as well as revivals and new plays such as The Odd Couple (2005), November (2008), Waiting for Godot (2009), The Nance (2013), It's Only a Play (2015), The Iceman Cometh (2015), The Front Page (2016), Angels in America (2018), Gary: A Sequel to Titus Andronicus (2019), and Pictures From Home (2023).

Lane has received six Tony Award nominations for his work on Broadway, winning three times for A Funny Thing Happened on the Way to the Forum (1996), The Producers (2001), and Angels in America (2018).

For his work on television Lane has received eight Primetime Emmy Award nominations for guest starring roles on Frasier, Mad About You, Modern Family, and The Good Wife and won for Only Murders in the Building.