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Guthrie was born on April 8, 1979, in Roseburg, Oregon. In high school, he played multiple sports, including baseball, football, and basketball. He was also class valedictorian. He also earned Eagle Scout rank with the Boy Scouts of America. Guthrie attended Brigham Young University and Stanford University, where he was a starting pitcher. He served a two-year mission for the LDS Church to Spain.
Guthrie is 6'1" tall and weighs 205 lbs. His 2011-2012 contract status is for one year at $5.75 million.
Guthrie spent most of the 2006 pro-ball season with the Triple-A Buffalo Bisons, but was twice called up to the majors to join the Cleveland Indians as a relief pitcher.  On January 19, 2007, Guthrie was designated for assignment and was picked up by the Baltimore Orioles. Later that year, Guthrie had become one of the best pitchers in the American League. This put him into consideration for the Rookie of the Year Award.
During the 2008 season, Guthrie emerged as the staff ace of the Baltimore Orioles. Guthrie pitched for Team USA in the 2009 World Baseball Classic.
Guthrie lives with his family in American Fork, Utah. He is an avid believer in living green, bicycles to work and recycles everything possible.