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Nelson started studying music from mail order material that his grandparents gave him. He wrote his first song at age seven and joined his first band at nine. During high school, he toured locally with the Bohemian Fiddlers as their lead singer and guitar player. After graduating from high school in 1950, he joined the Air Force. However, he was discharged due to back problems. After his return, Nelson attended Baylor University for two years but dropped out because he was succeeding in music. During this time, he worked as a disc jockey in Texas radio stations and a singer in honky tonks. Nelson moved to Vancouver, Washington, where he wrote "Family Bible" and recorded the song "Lumberjack" in 1956. In 1960, he signed a publishing contract with Pamper Music which allowed him to join Ray Price's band as a bassist. During that time, he wrote songs that would become country standards, including "Funny How Time Slips Away", "Hello Walls", "Pretty Paper", and "Crazy". In 1962, he recorded his first album, And Then I Wrote. Due to this success, Nelson signed in 1965 with RCA Victor and joined the Grand Ole Opry.

Nelson is a major liberal activist and the co-chair of the advisory board of the National Organization for the Reform of Marijuana Laws, which is in favor of marijuana legalization. On the environmental front, Nelson owns the bio-diesel brand Willie Nelson Biodiesel, which is made from vegetable oil. He is the co-founder and president of Farm Aid, and has been contributing to the benefit concert series since the first event in 1985, organizing concerts and performing with other prominent artists. Nelson is also the Honorary Chairman of the Advisory Board of the Texas Music Project, the official music charity of the state of Texas.