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Despite his two cancelled TV series and flops like View From the Top and the made-for-TV movie Perfect Strangers during his post–West Wing run, Lowe found success in the TV miniseries genre.
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 June 2006, he was the guest host for an episode in the third series of The Friday Night Project for the United Kingdom's Channel 4.
Lowe has also appeared in a televised advertisement for 'Visit California', along with other celebrities including Governor Arnold Schwarzenegger.
Lowe is currently teaming up with 44 Blue to produce a reality series entitled Potomac Fever about young adults living in Washington, D. In 2011, Lowe guest starred in a recurring role on Showtime's comedy Californication.
Lowe featured as the troubled but in-demand actor Eddie Nero – a character based upon "about ten people", according to Lowe During his promotional tour for Stories I Only Tell My Friends, Lowe told Australian radio show The Kyle & Jackie O Show that during his five-day press visit to Australia in 1990, he was so badly affected by the overuse of painkillers that the only two things he remembers from the trip were being at the Sydney Zoo and getting a tattoo, although he states in his book that he does not remember getting the tattoo.
Unhappy with the stories and his lack of screen time in the fourth season, Lowe announced he would leave.
In an episode broadcast on May 16, 2010, his character was part of a multi-vehicle crash involving a large truck and was put into a coma, the storyline was wrapped up in the first episode of the fifth season; Lowe did not appear in the episode.
He continued to appear in the series until the end of the 2009–10 season.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.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 the advertisement campaign, he was usually pictured in a white tee-shirt printed with the California state flag.) Lowe had a supporting role in the 2009 movie The Invention of Lying In 2010, he appeared in the biography of the Brat Packers called: Brat Pack: Where Are They Now?He also appeared on The Tonight Show with Conan O'Brien.
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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).