Belleville, Illinois high school friends Tweedy and Farrar started Uncle Tupelo as the Primitives in St. Louis in the mid-'80s. After a run of four albums (including their seminal debut, No Depression), Farrar abruptly quit in 1994 and started Son Volt, who continued Tupelo's spirit of moody and rousing ruralism. Tweedy and the remaining Tupelo members picked up as Wilco. With that group, Tweedy would permanently lay to rest the impression that Farrar had been the sole dark genius of Uncle Tupelo. (In fact, one theory holds that Farrar disintegrated the group because he was threatened by Tweedy's burgeoning creative role.)

Wilco's first album, A.M. (1995), seemed designed to please the Uncle Tupelo audience. However, the following two-disc Being There (1996), a sprawling achievement that garnered comparisons to the Rolling Stones' Exile on Main Street, and the experimental but pop-oriented Summerteeth (1999) would establish Tweedy as a distinct and formidable force in popular music.

Tweedy has also been part of Golden Smog, an all-star collective who has included members of the Jayhawks, Soul Asylum, and Big Star; appeared on the Handsome Family album Through the Trees; and also appeared on Blue Rodeo leader Jim Cuddy's solo debut, All in Time. In addition, Wilco collaborated with Billy Bragg on the two Mermaid Avenue albums, which set music to the lost lyrics of Woody Guthrie. In 2000 and 2001, Tweedy undertook a series of solo acoustic shows and formed a side group with Jim O'Rourke and Glenn Kotche, Loose Fur, before settling in to work on the next Wilco album. Unfortunately, Wilco found themselves without a label when Reprise Records rejected their album, Yankee Hotel Foxtrot, though they opted to tour in spite of this situation. After streaming the album for fans on Wilco's website, Nonesuch stepped in and gave Yankee Hotel Foxtrot an early 2002 release, and the album became a critical and commercial success. That same year, Tweedy wrote and recorded some solo material for Ethan Hawke's film Chelsea Walls, which became the backbone of movie's soundtrack album.

During his downtime with Wilco, Tweedy worked in the studio with the Minus 5, Beck, and Charlie Louvin, while serving as producer on recordings by Mavis Staples and Low, and he released a live album in 2006 drawn from a live performance, Sunken Treasure: Live in the Pacific Northwest. In 2013, Tweedy began writing and recording songs for a solo project which became a family affair when his teenage son, Spencer Tweedy, began playing drums on the sessions. The father/son band adopted the name Tweedy, and their debut album, Sukierae, was released in 2014, the same year Wilco released a pair of archival albums and played residencies in several cities to celebrate their 20th anniversary. ~ Erik Hage & Mark Deming