What with the Levan connection, it wasn't long before he was headhunted to become the resident DJ at Chicago's Warehouse, a predominately gay and black club where he became a local pin-up for his sets of sublime soulful disco. Playing records that even the hardened Chicagoan disco DJs had never heard of, his reputation shot skyward, but in 1983 he decided to leave the Warehouse and start his own club called Powerplant.

The venture was successful, but Frankie's mind was already on getting into music production, and just three years later, the club closed, and Frankie started putting records out. His first 12-inch was a cover of Teddy Pendergrass' "You Can't Hide," which he produced alongside Chip E and Joe Smooth and put out on Rocky Jones' DJ International imprint, but his biggest hit came the following year when he updated Jamie Principle's "Your Love" on Trax Records. Even though Jamie's track had been circulating on tape for years (and is disputed to be the first house music track ever recorded), many people attributed the record to Frankie (Larry Sherman's decision to capitalize on his popularity by labeling the record "Frankie Knuckles presents" and not mentioning Principle didn't exactly help matters), and from then on he was a name to be reckoned with on the international house music scene.