Before Run—D.M.C., Simmons was the lead vocalist in the hip-hop group called, "The Force." He founded Run-D.M.C. as a lead vocalist along with friend Darryl "DMC" McDaniels and the late DJ Jason "Jam-Master Jay" Mizell. The group's work is universally considered to be among the most pioneering and revolutionary in early hip-hop. Run began using the stage name of "Rev. Run" after he was ordained as a minister in Zoë Ministries. His first work as Rev. Run was a feature in the single "Song 4 Lovers" by UK pop band Liberty X in September 2005. The music video for that song was directed by Bill Schacht for Aestheticom and reached broadcast airplay chart positions of #2 Box UK and #4 MTV UK with heavy rotation on 5 other music channels in the UK.

It was followed by his first solo album, Distortion. The first single from the album, "Mind on the Road", is featured in the EA Sports's Madden NFL 06 video game. "Mind on the Road" uses samples from the song "I Love Rock 'n' Roll", in the tradition of Run-DMC's 1980s hits using samples like Aerosmith's hit "Walk This Way"

Rev Run appears on the MTV series Run's House, a reality show revolving around his everyday life with his family. Although the show does not air his first wife who he says "he does not like to speak with".

In 2002, he appeared on a special "Rap Stars" edition of The Weakest Link and ended up being the third one voted off.

In 2007, he appeared with his son Diggy Simmons on My Super Sweet 16 while attending a 16th birthday party for Diddy's son, Quincy. Diddy is also the producer of Run's House.

In 2008, Simmons and his wife Justine teamed up with Kool-Aid and a non-profit organization called KaBOOM! to help build playgrounds in underserved communities. With Kool-Aid, they are helping to build twenty four playgrounds over the course of 2008 and hope to raise awareness for the need for safe play spaces.

On August 5, 2008 Gotham Press published Simmons' book, Take Back Your Family: A Challenge to America's Parents, co-authored by his wife, Justine Simmons, and Chrisifer Morrow

On September 8th, 2007, Rev Run was honored as a BMI Icon at the annual BMI Urban Awards.

Simmons married Valerie Vaughn in 1983, and had three children with her, Vanessa Simmons, Angela Simmons, and Joseph Simmons Jr.

He married Justine Jones on June 25, 1994. With her, he had three more children: Daniel "Diggy" Simmons III, Russell "Russy" Simmons II, and Victoria Anne Simmons. Victoria died shortly after birth on September 26, 2006. Victoria was four pounds, five ounces when she was delivered via caesarean section. She died shortly after being born reportedly due to omphalocele, a birth defect that caused her organs to grow outside her body . The Simmons family decided to allow camera crews (of Run's House) to be in the hospital room as they broke the news to their children. They wanted to show viewers how, as a family, they dealt with such a situation. Soon they adopted a baby girl named Miley Justine Simmons.

The Simmons family lives in Saddle River, New Jersey, USA.

Solo

With Run-D.M.C.