His passing was confirmed by longtime business partner Frederick Dunson, who told the Chicago Tribune that Knuckles had "died unexpectedly this afternoon at home." While details are forthcoming, Knuckles had been living with late-breaking Type II diabetes.

Knuckles was known as "The Godfather of House," among the cornerstones of house music and culture through his legendary DJ residences at Chicago clubs like Power Plant and the Warehouse, where he'd spin a wildly diverse range of music re-edited for maximum dance-floor impact. His signature style became known as the Warehouse sound and was the original source of the term "house music." In 2004, a portion of Jefferson Street in Chicago where the Warehouse once stood was renamed "Frankie Knuckles Way."