They signed with a small record company there, but never really put out anything that sold well. Then, they put out their first hit single Shout! in 1959. They followed that success with Twist and Shout in 1962. However, when the record company wanted them to do Surf and Shout, they figured it was time to move on.

In 1963, they started their own record label, T-Neck, to have more control over their work. They also added a new kid to play lead guitar named Jimi Hendrix. However, after struggling for a couple of years with their own label, they signed with Motown in 1965. Attempting to put the Isleys in their "formula", the hit factory only produced one hit for the brothers, This Old Heart of Mine.

The Isleys left Motown in 1968 and in 1969, restarted their own T-Neck label, which is where most of their excellent work comes from. They also won a Grammy for It's Your Thing.

In 1973, younger brothers, Ernie (3/7/52) and Marvin (8/18/53) , along with cousin, Chris Jasper (12/30/51), officially joined the group producing the album, 3 + 3. This was the beginning of the famous "Isley Brothers sound" that is prevalent in the majority of their recordings in the 70s, 80s and 90s. From 1973 to 1983, the Isley Brothers had nine consecutive gold or platinum albums.

In 1984, the younger members of the group decided to strike out on their own, forming Isley, Jasper, Isley. That left the group consisting of the original threesome. In 1985, the original threesome signed with Warner Brothers Records. But, on March 31 of the following year, O' Kelly died of an unexpected heart attack, shrinking the original group to only two members.

The future Mrs. Ronald Isley, Angela Winbush, started assisting in the writing and producing for the Isley Brothers in 1987 with the Smooth Sailin' album. The Isley Brothers delivered Tracks of Life in 1992, with Marvin and Ernie rejoining brother Ronnie. And the next year, they released their outstanding Live! album.

The Isley Brothers have appeared on movie soundtracks in the late 90s. In 1995, they were on the soundtrack for Friday featuring Ice Cube and Chris Tucker with their song, Tryin' to See Another Day. And in 1996, they performed Let's Lay Together on the soundtrack for the Wayans Brothers' Don't Be a Menace to Society While Drinking Your Juice in the Hood. This song is also featured on their 1996 album, Mission to Please which features producers, Angela Winbush, R. Kelly, Babyface, and Keith Sweat.

In 2001, the Isley Brothers released 'Eternal' featuring songs with artists such as R. Kelly and Jill Scott. Ernie Isley gets to do more of what he is famous for on this album, especially in "Ernie's Jam." Also, Ron Isley works on more guest appearances with performers such as Foxy Brown, JaRule, and Keith Sweat.