Reputedly the first rock and roll single, Jackie Brenston and his Delta Cats' "Rocket 88" was recorded there in 1951 with song composer Ike Turner on keyboards, leading the studio to claim status as the birthplace of rock & roll. Blues and R&B artists like Howlin' Wolf, Junior Parker, Little Milton, B.B. King, James Cotton, Rufus Thomas, and Rosco Gordon recorded there in the early 1950s.

Rock and roll, country music, and rockabilly artists, including Johnny Cash, Elvis Presley, Carl Perkins, Roy Orbison, Charlie Feathers, Ray Harris, Warren Smith, Charlie Rich, and Jerry Lee Lewis, recorded there throughout the mid-to-late 1950s until the studio outgrew its Union Avenue location. Sam Phillips opened the larger Sam C. Phillips Recording Studio, better known as Phillips Recording, in 1959 to replace the older facility. Since Phillips had invested in the Holiday Inn Hotel chain earlier, he also recorded artists starting in 1963 on the label Holiday Inn Records for Kemmons Wilson. In 1957, Bill Justis recorded his Grammy Hall of Fame song "Raunchy" for Sam Phillips and worked as a musical director at Sun Records.

In 1969, Sam Phillips sold the label to Shelby Singleton, and there was no recording-related or label-related activity again in the building until the September 1985 Class of '55 recording sessions with Carl Perkins, Roy Orbison, Jerry Lee Lewis, and Johnny Cash, produced by Chips Moman.

In 1987, the original building housing the Sun Records label and Memphis Recording Service was reopened, by Gary Hardy as "Sun Studio," a recording label and tourist attraction that has attracted many notable artists, such as U2, Def Leppard, Bonnie Raitt, and Ringo Starr.

After the museum closes at night, the studio is sometimes still and active recording studio for those who would like to go and record using the vintage equipment that was present during the time the studio was fully operational. Sometimes at night, other unknown things can happen as well. Stories of footsteps echoing upstairs at night float around the room at night, and Sonny himself claims to have been touched by somebody who wasn't there while on a studio tour.