His longtime friend and former producer Alvin Toney told New York's Daily News that Mack had been ill for some time and knew he did not have long to live.
Mack's cause of death has been confirmed as heart failure and reportedly he passed away in a hospital near his SC home on Monday.
'God bless my friend.
Fellow musicians such as Evidence, Boi-1da, Pharoahe Monch, Termanology, Roc Marciano, Joe Budden, and R.A. the Rugged Man have paid tribute on Twitter.
Referencing the lyrics of Flava In Ya Ear, he added: "May he kick that ol' robotic, futuristic, George Jetson insane [expletive] in the infinite". The song featured a video by Hype Williams - whose clips for Missy Elliott, Diddy and others would define the look of mid-1990s hip-hop - and a remix with Notorious B.I.G.
Biz Markie, Funkmaster Flex, and DJ Scratch are among the rappers and DJs who've mourned his passing.
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The now-classic "Flava In Ya Ear", would go on to peak at no. 9 on the Billboard Hot 100, be certified platinum, and grab a nomination for Best Rap Solo Performance at the 37th Grammy Awards.
Toney had visited Mack at his church in Walterboro to film a documentary about his life and career. In a 1995 profile with The New York Times, Diddy called him "hip-hop's George Clinton, because his stuff is really off the wall. He wasn't scared. He was ready".
'I wanted the world to know the talent he had. "It was something I wanted people to enjoy, but it was cut short because he was very religious and wanted to go to church".
According to EPMD's Erick Sermon, Mack was also working on a new album.
Mack may have been something of a one-hit wonder, but his historic ties to rap royalty made him a familiar presence, and fans were quick to offer his family-he leaves behind a wife and two adult children-warm support.