According to reports, the DJ had struggled with Type 2 diabetes. However, he had continued to work — including performances abroad — and had a schedule of upcoming appearances listed online.
Born Francis Nicholls in New York, Knuckles and his friend Larry Philpot (who would become DJ Larry Levan) began hitting disco dance clubs in their teens to learn the craft.
Knuckles moved to Chicago in the 1970s and became a fixture of that city's club scene. As the era of disco began to fade, he began experimenting with extending R&B songs by artists such as Michael Jackson and Whitney Houston and mixing them with indie soul tracks, drum machine loops and songs from other genres or European artists.
The new sound became known as house music.
The influential DJ was renowned for his pioneering sessions at Chicago dance clubs The Music Box and The Warehouse before eventually opening The Power Plant, his own venue highlighting house music, in 1982.
He also served as a prolific producer and high-profile remixer, working with artists such as Jackson, Diana Ross, Chaka Khan, Robert Owens and Jamie Principle. He won a Grammy Award in 1997 in the category of remixer of the year (non-classical).
In 2004, Chicago honoured the DJ by renaming a portion of Jefferson Street, near the former site of The Warehouse, Frankie Knuckles Way. The following year, he was inducted into the Dance Music Hall of Fame.
Fans, colleagues and recording artists — from the Wu Tang Clan to Questlove of The Roots — have been sharing their memories and tributes to the DJ online.
“Frankie Knuckles was so underappreciated,” Questlove Jenkins of The Roots posted via Twitter. “He was the DJ that DJs aspired to be. True dance pioneer.”
Chicago Mayor Rahm Emanuel said Tuesday that Chicago has lost "one of its most treasured cultural pioneers."
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