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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.
He also appeared on The Tonight Show with Conan O'Brien.
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.
In addition to his 2001 Emmy nomination for The West Wing, He is of German, English, Irish, Scottish, and Welsh ancestry. , Lowe found out that one of his ancestors, Christopher East, was a Hessian soldier.
Eventually, Lowe left the series, not long before Sorkin and director/executive producer Thomas Schlamme unceremoniously quit over a dispute with NBC.
During the final season of The West Wing, Lowe returned to his role of Sam Seaborn, appearing in two of the final four episodes.