Born in Oakland, California, Sheila E. is the daughter of Juanita Gardere, a dairy factory worker, and percussionist Pete Escovedo, with whom she frequently performs. Her mother is Creole-French/African mix, and her father is of Mexican origin. Sheila E's uncle is Alejandro Escovedo, and Tito Puente was Escovedo's godfather. She also is niece to Javier Escovedo, founder of seminal San Diego punk act The Zeros.

In 2006, Sheila formed a female group C.O.E.D. (Chronicles of Every Diva) consisting of Sheila E., Kat Dyson, Rhonda Smith and Cassandra O'Neal. The group released a single "Waters of Life". In March 2007, the group went on a successful tour in Europe and Japan. The group toured overseas in 2008 and released a CD available in limited distribution or through her website. For several concerts she was joined by Candy Dulfer, who was billed as a special guest. She performed at the 2007 Latin Grammy Awards with Juan Luis Guerra. She also performed at the ALMA (American Latin Music Awards) Awards in June 2007 with Prince, and on July 7, 2007 in Minneapolis with Prince. She performed at all three of his concerts: first, at Prince's 3121 perfume launch at Macy's, followed by the Target Center concert, and finally, at an aftershow at First Avenue. In October 2007, Sheila E. was a judge alongside Australian Idol judge and marketing manager Ian "Dicko" Dickson and Goo Goo Dolls lead singer John Rzeznik on the Fox network's The Next Great American Band.  Sheila E. once again teamed up with Prince in March 2008, as she sat in (and played keyboard) on the performance with her family at Harvelle Redondo Beach. On April 9, 2008, Sheila E. appeared on the Emmy winning program, Idol Gives Back. Sheila E. took part in the show opener "Get on Your Feet" with Gloria Estefan. Dance troupe, So You Think You Can Dance finalists joined them on stage. On April 26, 2008, Sheila E., along with Morris Day and Jerome Benton, performed with Prince at the Coachella Music Festival. From May 2 to 6, 2008, Sheila E. played four sold-out shows at Blue Note Tokyo, the most frequented jazz music club in Tokyo, Japan.  On June 14, 2008, Sheila E. performed at the Rhythm on the Vine music and wine festival at the South Coast Winery in Temecula, California for Shriners Hospital for Children. She took the stage with the E Family, Pete Escovedo, Juan Escovedo and Peter Michael Escovedo. Other performers at the event were jazz musician Herbie Hancock, contemporary music artist Jim Brickman and Kirk Whalum.

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