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That same year, Lowe filmed Stir of Echoes: The Homecoming, the sequel to the 1999 Kevin Bacon thriller Stir of Echoes.
In 2006, it was announced that Lowe would join the cast of Brothers & Sisters for a guest run of several episodes.
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–).
Thereafter, his film career decreased and he ventured into television, making his breakthrough as Sam Seaborn on the NBC political drama The West Wing (1999–2003), for which he received a Primetime Emmy Award nomination and two Golden Globe Award nominations.
After leaving the show, Lowe was the star and executive producer of a failed NBC drama, The Lyon's Den (2003). Although Lowe had expressed unhappiness about his decreased role on that show at the time of his departure, he has now repeatedly said that any animosity between them is over and that he was pleased to be working once more with Sorkin, whose talents as a writer Lowe highly regards. Derek Shepherd of Grey's Anatomy, which eventually went to Patrick Dempsey.
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 his autobiography Stories I Only Tell My Friends, he wrote regarding Sheen, "We were both nerds [...] he wanted to be a baseball player." One of Lowe's earliest roles came in the 1983 TV film Thursday's Child, for which he received his first Golden Globe Award nomination for Best Supporting Actor in a Series, Miniseries, or Television Film.
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).
The year 2004 marked his return to this genre; he had appeared in 1994's The Stand, based on Stephen King's book of the same name.
In 2004 Lowe starred in the TNT remake of the Stephen King miniseries Salem's Lot which was the highest rated cable program of that summer and the highest ratings TNT original programming had at the time.