The label has featured artists such as Slayer, the Black Crowes, ZZ Top, Danzig, Trouble, Tom Petty, Johnny Cash, The Mother Hips, and System of a Down.

Among the first acts to be signed were Slayer (which followed Rubin from Def Jam), Danzig, The Four Horsemen, Masters of Reality, and Wolfsbane, as well as indie rockers the Jesus and Mary Chain and controversial stand-up comedian Andrew Dice Clay.

Def American had its first major success with The Black Crowes' 1990 debut album, Shake Your Money Maker, which was eventually certified quintuple platinum by the RIAA.

Rapper Sir Mix-a-Lot obtained a number-one hit with the song "Baby Got Back" as well as a platinum-selling album titled Mack Daddy.

The guest list included Black Panthers with prop shotguns, The Amazing Kreskin, Tom Petty and Rosanna Arquette, The Red Hot Chili Peppers' Flea, Sir Mix-a-Lot, and Warner Bros. Records chairman (and pallbearer) Mo Ostin, with Reverend Al Sharpton presiding.

American had several sub-labels over the years, including Onion Records, Ill Labels, Wild West, Whte Lbls, and Infinite Zero.

However, sub-label Ill Labels was distributed by hip-hop specialist and former Warner Bros. subsidiary Tommy Boy Records as part of its deal.

However, American's current roster (except Tom Petty) was transferred to BMG successor Sony BMG (now known as Sony Music Entertainment) in mid-2007 after a legal battle between Warner and Rubin over the details of their former arrangement, in which American Recordings would sign and provide creative services for artists, while Warner Bros. was only to handle promotion, sales, marketing, and distribution because Rubin was prompted to move his label with his appointment to co-chairman of Columbia Records in the spring of 2007.