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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.

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.