While James was on tour with Richard, pop singer Georgia Gibbs recorded a version of James's song, which was released under the title "The Wallflower" and became a crossover hit, reaching number one on the Billboard Hot 100, which angered James. After leaving the Peaches, James had another R&B hit with "Good Rockin' Daddy" but struggled with follow-ups. When her contract with Modern came up for renewal in 1960, she signed a contract with Chess Records instead. Shortly afterward she was involved in a relationship with the singer Harvey Fuqua, the founder of the doo-wop group the Moonglows.
Dueting with Harvey Fuqua, James recorded for Argo Records (later renamed Cadet Records), a label established by Chess. Her first hit singles with Fuqua were "If I Can't Have You" and "Spoonful". Her first solo hit was the doo-wop–styled rhythm-and-blues song "All I Could Do Was Cry", which was a number two R&B hit. Chess Records co-founder Leonard Chess envisioned James as a classic ballad stylist who had potential to cross over to the pop charts and soon surrounded the singer with violins and other string instruments. The first string-laden ballad James recorded was "My Dearest Darling" in May 1960, which peaked in the top five of the R&B chart. James sang background vocals for her labelmate Chuck Berry on his "Back in the U.S.A."
Her debut album, At Last!, was released in late 1960 and was noted for its varied selection of music, from jazz standards to blues to doo-wop and rhythm and blues (R&B). The album included the future classic "I Just Want to Make Love to You" and "A Sunday Kind of Love". In early 1961, James released what was to become her signature song, "At Last", which reached number two on the R&B chart and number 47 on the Billboard Hot 100. Though the record was not as successful as expected, her rendition has become the best-known version of the song. James followed that with "Trust in Me", which also included string instruments. Later that same year, James released a second studio album, The Second Time Around. The album took the same direction as her first, covering jazz and pop standards and with strings on many of the songs. It produced two hit singles, "Fool That I Am" and "Don't Cry Baby".
James possessed the vocal range of a contralto. Her musical style changed during the course of her career. At the beginning of her recording career, in the mid-1950s, James was marketed as an R&B and doo-wop singer. After signing with Chess Records in 1960, James broke through as a traditional pop-styled singer, covering jazz and pop music standards on her debut album, At Last! James's voice deepened and coarsened, moving her musical style in her later years into the genres of soul and jazz.