In 1963, then about to give birth to daughter Whitney Houston, she formed the Sweet Inspirations with Doris Troy and niece Dee Dee Warwick. Later, under contract to Atlantic Records, Sylvia Shemwell, Estelle Brown and Myrna Smith form the line-up. During the mid-1960s, the Sweet Inspirations provided backup vocals for a variety of artists, including Otis Redding, Wilson Pickett, Lou Rawls, The Drifters, Dusty Springfield and Houston's niece Dionne Warwick. They appeared on Van Morrison's single Brown Eyed Girl. Houston performed the operatic soprano melody on the Aretha Franklin hit, Ain't No Way. In 1967, The Sweet Inspirations sang background vocals for The Jimi Hendrix Experience on the track "Burning of the Midnight Lamp".
As Cecily Blair she cut her first secular solo record "This Is My Vow" on M'n'M Records in 1963 following this up in 1966 with "Bring Him Back" b/w "World Of Broken Hearts" on Congress. Her final solo single before recording with The Sweet Inspirations was "Don't Come Running To Me" b/w "One Broken Heart For Sale" released on Kapp Records in 1967. On these early singles her name is spelled as Sissie Houston. In 1969, Houston signed a recording contract with Commonwealth United Records and recorded her solo debut LP Presenting Cissy Houston which was released in 1970. It contained several well received singles, including covers of "I'll Be There" and "Be My Baby", both of which made the R&B charts.
Houston's versatile cross-genre singing style has kept her highly in demand as a session musician with some of the world's most successful recording artists. Houston, along with Dionne Warwick and Dee Dee Warwick, sang the background vocals on the original recording of Time Is On My Side by Kai Winding, released by Verve Records in October 1963. She was one of the backup singers on the Paul Simon song "Mother and Child Reunion" (1972)