He played an important role in developing and popularizing house music in Chicago during the 1980s, when the genre was in its infancy. In 1997, Knuckles won the Grammy Award for Remixer of the Year, Non-Classical. Due to his importance in the development of the genre, Knuckles was often known as "The Godfather of House Music."
Born in The Bronx, Knuckles and his friend Larry Levan began frequenting discos as teenagers during the 1970s. While studying textile design at the FIT, Knuckles and Levan began working as DJs, playing soul, disco, and R&B at two of the most important early discos, The Continental Baths and The Gallery. In the late 1970s, Knuckles moved from New York City to Chicago, where Robert Williams, an old friend was opening what became the Warehouse. When the Warehouse club opened in Chicago in 1977, he was invited to play on a regular basis, which enabled him to hone his skills and style. This style was a mixture of disco classics, unusual indie-label soul, the occasional rock track, European synth-disco and all manner of rarities, which would all eventually codify as "House Music." The style of music now known as house was named after a shortened version of the Warehouse.
Knuckles was so popular that the Warehouse, initially a members-only club for largely black gay men, began attracting straighter, whiter crowds, leading its owner, Robert Williams, to eschew membership. He continued DJing at the Warehouse until November 1982, when he started his own club in Chicago, The Power Plant.
Around 1983, Knuckles bought his first drum machine to enhance his mixes from Derrick May, a young DJ who regularly made the trip from Detroit to see Knuckles at the Warehouse and Ron Hardy at the Music Box, both in Chicago. The combination of bare, insistent drum machine pulses and an overlay of cult disco classics defined the sound of early Chicago house music. A sound which many local producers began to mimic in the studios by 1985.
When the Power Plant closed in 1987, Knuckles played for four months at Delirium in the United Kingdom. Chicago house artists were in high demand and having major success in the UK with this new genre of music. Knuckles also had a stint in New York, where he continued to immerse himself in producing, remixing, and recording. 1988 saw the release of Pet Shop Boys' third album, Introspective, which featured Knuckles as a co-producer of the song "I Want a Dog."
In 1982, Knuckles was introduced to then-unknown Jamie Principle by mutual friend Jose "Louie" Gomez, who had recorded the original vocal-dub of "Your Love" to reel-to-reel tape. Louie Gomez met up with Frankie at the local record pool (I.R.S.) and gave him a tape copy of the track. Knuckles played Gomez's unreleased dub mix for an entire year in his sets during which it became a crowd favorite. Knuckles later went into the studio to re-record the track with Principle, and in 1987 helped put Your Love and Baby Wants to Ride out on vinyl after these tunes had been regulars on his reel-to-reel player at the Warehouse for a year.
As house music was developing in Chicago, producer Chip E. took Knuckles under his tutelage and produced Knuckles' first recording, "You Can't Hide from Yourself" Then came more production work, including Jamie Principle's "Baby Wants to Ride", and later "Tears" with Robert Owens (of Fingers Inc.) and (Knuckles' protégé and future Def Mix associate) Satoshi Tomiie.
Knuckles made numerous popular Def Classic Mixes with John Poppo as sound engineer, and Knuckles partnered with David Morales on Def Mix Productions. His debut album Beyond the Mix (1991), released on Virgin Records, contained what would be considered his seminal work, "The Whistle Song", which was the first of four number ones on the US dance chart. The Def Classic mix of Lisa Stansfield's "Change", released in the same year, also featured the whistle-like motif. Another track from the album, "Rain Falls", featured vocals from Lisa Michaelis. Eight thousand copies of the album had sold by 2004. Other key remixes from this time include his rework of the Electribe 101 anthem "Talking with Myself" and Alison Limerick's "Where Love Lives".
When Junior Vasquez took a sabbatical from The Sound Factory in Manhattan, Knuckles took over and launched a successful run as resident DJ. He continued to work as a remixer through the 1990s and into the next decade, reworking tracks from Michael Jackson, Luther Vandross, Diana Ross, Eternal and Toni Braxton. He released several new singles, including "Keep on Movin'" and a re-issue of an earlier hit "Bac N Da Day" with Definity Records. In 1995, he released his second album titled Welcome to the Real World. By 2004, 13,000 copies had sold.
Knuckles played as resident DJ at Genesis (Osaka, Japan) for one year (probably in the late 1980s or early 1990s).
Openly gay, Knuckles was inducted into the Chicago Gay and Lesbian Hall of Fame in 1996.
In 2004, Knuckles released a 13-track album of original material – his first in over a decade – titled A New Reality. In October 2004, "Your Love" appeared in the videogame Grand Theft Auto: San Andreas, playing on house music radio station, SF-UR.
In the mid-2000s, Knuckles developed Type II diabetes. On March 31, 2014, he died of complications from the disease in Chicago at age 59.
In April 2015, a year after his death, Defected Records released a retrospective compilation, House Masters Frankie Knuckles; Knuckles had selected the track list before his death. Also, the same month, as a tribute to Knuckles, a version of his song "Baby Wants to Ride" was released by Underworld and Heller & Farley to mark the year anniversary of his passing. It went straight to number one on the UK's first ever Official Vinyl Singles Chart. All proceeds will go to the Frankie Knuckles Trust / Elton John AIDS Foundation. A year after his death, on April 4, 2015, In Memoriam Essential Mix on BBC Radio 1 was played, containing two, previously unreleased Knuckles mixes.
In 1997, Knuckles won the Grammy Award for Remixer of the Year, Non-Classical. In 2004, the city of Chicago – which "became notorious in the dance community around the world for passing the so-called 'anti-rave ordinance' in 2000 that made property owners, promoters and deejays subject to $10,000 fines for being involved in an unlicensed dance party" – named a stretch of street in Chicago after Knuckles, where the old Warehouse once stood, on Jefferson Street between Jackson Boulevard and Madison Street. That stretch of street, called Frankie Knuckles Way, "was renamed when the city declared 25 August 2004 as Frankie Knuckles Day. The Illinois state senator who helped make it happen was Barack Obama." In 2005, Knuckles was inducted into the Dance Music Hall of Fame for his achievements.
Knuckles was featured in the documentary films Maestro (2003), written and directed by Josell Ramos, The UnUsual Suspects: Once Upon a Time in House Music (2005), directed by Chip E. and Continental (2013) about the Continental Baths.
October 2004, "Your Love" appeared in the videogame Grand Theft Auto: San Andreas, playing on house music radio station, SF-UR."Rain Falls" (single)
"You Can't Hide from Yourself" – CBS Records
"Tears" (single) Frankie Knuckles presents Satoshi Tomiie – FFRR
"Your Love/Baby Wants to Ride" – Trax Records
Beyond the Mix – Virgin Records
"The Whistle Song" – Virgin Records
Sessions Six – Mixed by Frankie Knuckles – Ministry of Sound
Choice: A Collection of Classics – Azuli Records
"Keep on Movin'" – Definity Records
"Change" – Lisa Stansfield
"Someday (I'm Coming Back)" – Lisa Stansfield
"Never, Never Gonna Give You Up" – Lisa Stansfield
"Let the Music (Use You)" - The Nightwriters
"Turn it Out" - Patti Labelle
"Deep Love" – Dada Nada (Robert Ozn) (Remixed by Knuckles and David Morales)
"Power of Love/Love Power" – Luther Vandross
"Left to My Own Devices" – Pet Shop Boys
"This Time" – Chanté Moore
"Happy" – Towa Tei
"Let No Man Put Asunder" – First Choice
"Ain't Nobody" – Chaka Khan
"Watcha Gonna Do with My Lovin'" – Inner City
"Talking with Myself" – Electribe 101
"The Pressure Part 1" – Sounds of Blackness
"Where Love Lives" – Alison Limerick
"I Want a Dog" – Pet Shop Boys
"Notgonnachange" – Swing Out Sister
"Time Will Tell" – Nu Shooz
"Because of Love" – Janet Jackson
"Love Hangover" – Diana Ross
"Let Me Wake Up In Your Arms" – Lulu
"Bring Me Love" – Andrea Mendez
"Rock with You" – Michael Jackson
"Scream" (remixed by Knuckles and David Morales) – Michael Jackson
"Thriller" (remixed by Knuckles and David Morales) – Michael Jackson
"You Are Not Alone" – Michael Jackson
"Closer Than Close" – Rosie Gaines
"Un-Unbreak My Heart" – Toni Braxton
"I Don't Want To" – Toni Braxton
"Sunshine" – Gabrielle
"Baby I" – Ariana Grande
"I'm Going to Go" – Jago
"Blind" – Hercules & Love Affair
"You've Got the Love" – The Source featuring Candi Staton
"Million Dollar Bill" – Whitney Houston
"Forever Came Today" – The Jackson 5 (Released On The Remix Suite)
"Wrong" – Depeche Mode
"Don't Wait" – Mapei
"Reflections" – Isabel Rose
"If I Fall" – Myon & Shane 54 with Cole Plante
"Can I Touch You There" – Michael Bolton