David Carr, on his book, titled "Torture-Free but Still a Rock Star", describes Nels Cline as "one of the best guitarists in any genre."

Cline began to play guitar at age 12 together with his twin brother, Alex Cline, who took up the drums. They played together in a youth rock band called "Homogenized Goo". Cline's activity began in 1977 and can be heared on over 150 albums of various genres, from jazz to rock and experimental music. His first appearance was on the Vinny Golia's album, "Openhearted" (1978), and his first solo work was "Angelica" (1988). Cline has played with jazz musicians such as, amongst others, Tim Berne, Charlie Haden, Vinny Golia, Wadada Leo Smith and Gregg Bendian. He has also performed and recorded with Mike Watt, with country music legend Willie Nelson, with the band "Banyan" together with Watt and ex-Jane's Addiction drummer Stephen Perkins, with "Geraldine Fibbers" with then-partner Carla Bozulich and with Sonic Youth frontman and guitarist, Thurston Moore. He frequently participates in jazz projects with his twin brother, Alex. Other Cline's projects are the jazz ensemble "The Nels Cline Singers", a free-improvisation group "the Acoustic Guitar Trio" and "Nels Cline Trio" founded In the late 1980s. Nels Cline joined alternative rock band Wilco in early 2004.