He got his start as a drummer and in 1969 hooked up with Harold Melvin and the Blue Notes.
He moved to the front as a vocalist soon after, and by 1971, the group had signed with legendary producers Kenny Gamble and Leon Huff at Philadelphia International Records.
The group scored such hits as "The Love I Lost," "Yesterday I Had the Blues" and "Wake Up, Everybody."
Pendergrass broke out on his own in 1976, and became the first black male singer in history to record five consecutive multi-platinum albums, according to his Web site.
After playing to sold-out shows around the globe, tragedy struck in 1982 when he lost control of his Rolls-Royce and crashed on Wissahickon Drive, resulting in severe spinal cord damage and paralyzing him from the waist down.
"They don't fill you with hope after something like this," Pendergrass told the Daily News in 2007.
"They tell you that your life is going to be shorter, but they don't know by how much."
He spent six months in a hospital after the accident but returned to recording the next year with the album "Love Language."
He released in 1985 "Working It Back," which was followed by "Joy" (1988), "Truly Blessed" (1990) "A Little More Magic" (1993) and "You and I" (1997).
Gamble and Huff, in a joint statement, said that Pendergrass was "one of the greatest artists that the music industry has ever known, and there hasn't been another one since.
"We've lost our voice and we've lost our best friend, but we're thankful for what we had," the statement read. "It was beautiful. He was one of the best."
Earlier, Huff reminisced during an interview aired on WDAS-FM about Pendergrass' first solo performance, which was at a club in California.
"That night I saw the coming of a superstar," Huff said. "When Teddy walked out on the stage, he didn't even open his mouth and the place went crazy with screaming females. He was just so dynamic, and when he started singing, he just blew them away."
Gamble noted what it was about Pendergrass that drove all those ladies crazy.
"He was tall dark and handsome," Gamble said. "He had a magnetism about him . . . He was injured 28 years ago and hung in there a long time. He was strong as a bull."
WDAS was playing a tribute to the late soul star Wednesday night.
Fans took to Facebook to lament the loss of one of R&B's greats.
Poster Michael Collins said: "This is a very sad day. Today, music will stand still for a King! God bless your soul . . . A piece of my history is now gone."
Another poster, Delia Desbois, wrote: "I've spent the most beautiful moments of my life thanks to his music . . . We will miss you. Rest in Peace."
Questlove of the Roots posted on Twitter: "sad loss. just heard the immortal Teddy Pendergrass has just gone to a better place. Soul will never be the same."
The Associated Press contributed to this report.