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In 2011, Lowe appeared on The Oprah Winfrey Show and stated that he left the show because he did not feel he was being respected, when the other lead characters received a raise and he did not. In 2005, he starred as Lieutenant Daniel Kaffee in a London West End production of Sorkin's play A Few Good Men, the first time the two had worked together since The West Wing.

In 2006, it was announced that Lowe would join the cast of Brothers & Sisters for a guest run of several episodes.

In January 2007, ABC announced that Lowe would be staying on Brothers and Sisters as a "special guest star" for the rest of Season 1 after Lowe's initial appearance on the show in November 2006 brought the best ratings and demographic showing for the show since its premiere.

His breakthrough role was his big screen debut in 1983, when he and Emilio Estevez were cast in Francis Ford Coppola's The Outsiders. Elmo's Fire, making them the two more prominent actors from the group known as the Brat Pack. followed, with Demi Moore (who had starred alongside Lowe in St. He then received his second Golden Globe Award nomination for Best Supporting Actor for his role as the mentally disabled Rory in Square Dance (1987).

Lowe played the role of Sodapop Curtis, the brother of the main character Ponyboy Curtis (C. In August 1987 he performed on stage, playing Baron Tusenbach in Chekov's The Three Sisters at The Williamstown Theatre Festival.

The series premiere received the highest ratings for a movie premiere in Lifetime history.

In that same year, Lowe filmed his role as a movie agent in the 2006 independent film Thank You for Smoking.

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He came to prominence as a teen idol in the 1980s, appearing in teen and young adult film roles in The Outsiders (1983), Oxford Blues (1984), St. Lowe appeared as Robert Mc Callister on the ABC television drama Brothers & Sisters (2006–2010), followed by a four-year run as Chris Traeger on the NBC sitcom Parks and Recreation (2010–14), for which he was critically acclaimed. Ethan Willis on the CBS medical drama Code Black (2015–) and appears with his two sons, Matthew and John Owen, in the A&E reality series The Lowe Files (2017–).

In 2006 he filmed The Perfect Day for TNT, in which he took a pay cut to film in New Orleans in order to help the hurricane-ravaged area.

That same year, Lowe filmed Stir of Echoes: The Homecoming, the sequel to the 1999 Kevin Bacon thriller Stir of Echoes.

But the acclaimed cast of the show—including Allison Janney, Richard Schiff, Dulé Hill, John Spencer, Bradley Whitford, Martin Sheen (whose President Bartlet was initially scripted as a small role) and Stockard Channing (whose First Lady was initially scripted as a guest role)— were all strong actors and eventually Lowe's character was no longer the lead.