During the early 1980s Whitley was busking on the streets of New York City and collaborating with musicians Marc Miller, Arto Lindsay and Michael Beinhorn. He was given a plane ticket to Ghent, Belgium in 1981, and lived there for six years, recording several albums and playing with the bands Kuruki, 2 Belgen, Nacht Und Nebel, Alan Fawn, and A Noh Rodeo.

In 1988, producer Daniel Lanois heard Whitley perform at the Mondo Cane club in New York City and he helped Whitley obtain a recording contract with Columbia Records. In 1991 two of Whitley’s songs charted on the Billboard Mainstream Rock charts: “Big Sky Country” (#36) and “Living with the Law” (#28).

In 2000, Whitley recorded his album Perfect Day, an album of cover songs, with Chris Wood and Billy Martin and followed up with the album Rocket House in 2001.

Whitley’s style drew on an array of influences. In 2001, The New York Times described him as “restless, moving into noise-rock and minimalist jazz evoking Chet Baker and Sonic Youth as much as Robert Johnson”. He recorded songs by Robert Johnson and Bob Dylan as well as Lou Reed, James Brown, J.J. Cale, The Clash, Nat King Cole, The Doors, Willie Dixon, The Flaming Lips, Jimi Hendrix, Howlin’ Wolf, The Jesus and Mary Chain, Kraftwerk, Gary Numan, The Passions, Prince, The Stooges, and Sonny Boy Williamson II.

Whitley’s song “Breaking Your Fall” from the album Hotel Vast Horizon (2003) won the 3rd Annual Independent Music Awards for Folk/Singer-Songwriter Song. In 2004 he won The 4th Annual Independent Music Award for Blues/R&B Song for his composition “Her Furious Angels” from the album War Crime Blues. Whitley was an inaugural member of The Independent Music Awards’ judging panel to support independent artists and collaborated with Jeff Lang on an album called Dislocation Blues in 2005.

In fall 2005, Whitley canceled his tour due to health issues. In November he was reported to be terminally ill with lung cancer and under the care of hospice. He died on November 20, 2005 in Houston, Texas at the age of 45. After his death, musician John Mayer said, “[Whitley’s] somewhat prostrated place in pop culture earned him a sidebar of an obituary, but to those who knew his work, it registers as one of the most underappreciated losses in all of music.” Whitley is survived by his brother Dan and his musician daughter, Trixie Whitley.