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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.

As an American POW, his ancestor was given a choice, and took the option to stay in the United States.

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.

He also appeared on The Tonight Show with Conan O'Brien.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.Soon after ABC announced an early Season 2 renewal for Brother & Sisters in March 2007, Lowe announced he would be returning for the show's second season.He continued to appear in the series until the end of the 2009–10 season.Lowe was drawn to the role because of his personal love of politics, and his longstanding personal relationship with Martin Sheen, who was cast as President Bartlet.

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