Buehrle began his professional career in 1999 with the White Sox' Single-A Burlington Bees. He went 7–4 with a 4.10 ERA that included a complete game shutout. Buehrle followed this up with an excellent year in 2000, going 8–4 with a 2.28 ERA for the Double-A affiliate Birmingham Barons in Hoover, Alabama, giving up only 17 walks in 119 innings. He would be named the Southern League's Most Outstanding Pitcher that season and was the winning pitcher in the Futures Game, then rated as the No. 8 prospect in the White Sox organization.