The drama had its American premiere March 18, 2000, at the Woolly Mammoth Theatre Company in Washington DC. Wilson Milam, who staged the London premiere of Bug, helmed the DC run. Deborah Hazlett, Brian Hemmingsen, Kate Norris, Eric Sutton and Stephen Schmidt starred in the darkly quirky play about a 40-year-old woman named Agnes who hides from her ex-con husband in the motel outside Oklahoma City. While partying with a girlfriend, she meets Peter, who begins to see bugs everywhere. Letts' Killer Joe was first produced by Hired Gun Productions in Chicago. It has since been performed at the Edinburgh Festival, in London, Sweden, Norway, Spain, Australia and Germany, and in 1999 completed a successful Off-Broadway revival whose various casts included Amanda Plummer, Scott Glenn, Lori Petty and Michelle Williams.

Letts' latest play, Man from Nebraska, recently began performances at Chicago’s Steppenwolf Theatre Company.