His most famous song, "Please Send Me Someone to Love", a number one R&B hit single in late 1950, described by the reviewer Bill Dahl as "a multi-layered universal lament",[3] was widely influential and recorded by many other singers.

[5] His career flourished as a string of six Top 10 R&B hits followed, like "Lost Love" and "The Big Question", confirming his status as a leading blues ballad singer[6] and "a true master at expressing his innermost feelings, laced with vulnerability and pathos".

[3] Mayfield performed at the 7th Annual Cavalcade of Jazz concert held at Wrigley Field in Los Angeles on July 8, 1951 produced by Leon Hefflin Sr. along with Billy Eckstine, Lionel Hampton, Jimmy Witherspoon and Joe Liggins, Roy Brown and his Honey Drippers.

[7] In 1952, at the height of his popularity, Mayfield was severely injured in an automobile crash, when he was returning from a performance in Las Vegas to Los Angeles as the front-seat passenger in a chauffeur-driven car.

[8] In 1961, Mayfield's song "Hit the Road Jack" brought him to the attention of Ray Charles, who signed him to his Tangerine Records, primarily as a songwriter.

Mayfield wrote "Hide nor Hair", "At the Club", "Danger Zone", and "But on the Other Hand, Baby" for Tangerine,[4] and Charles, who had him signed to a five-year contract as his private songwriter,[9] recorded at least 15 of his songs.

[2] He also had a series of single releases as a vocalist on Tangerine, produced by Charles, including a remake of "River's Invitation", which crept into the Billboard Hot 100 but reached number 25 on the R&B chart in 1963.