Shady Records and D12

As Eminem succeeded in multi-platinum record sales, Interscope granted him his own record label. He and his manager Paul Rosenberg created Shady Records in late 1999. He followed this by signing his own Detroit collective D12 and rapper Obie Trice to the label. In 2002, Eminem signed 50 Cent through a joint venture between Shady and Dr. Dre's Aftermath label. In 2003, Eminem and Dr. Dre signed Atlanta rapper Stat Quo to the Shady/Aftermath roster. DJ Green Lantern, the former DJ for Eminem, was signed to Shady Records until a dispute related to the 50 Cent and Jadakiss feud forced him to depart from the label; he is no longer associated with Eminem. The Alchemist is now officially Eminem's tour DJ. In 2005, Eminem signed another Atlanta rapper, Bobby Creekwater, to his label along with West Coast rapper Cashis.

On December 5, 2006, Shady Records released compilation album, Eminem Presents: The Re-Up. It started out as a mixtape but Eminem found that the material was better than expected and released it as a full album. It was meant to help launch the new artists under the roster, like Stat Quo, Cashis and Bobby Creekwater. Around the time of recording Infinite, Eminem and rappers Proof and Kon Artis gathered the group of rappers now collectively in the group D12, short for "Detroit Twelve" or "Dirty Dozen", performing in the manner of the multi-man group Wu-Tang Clan. In 2001, Eminem brought his rap group, D12, to the popular music scene, and the group's debut album Devil's Night came out that year. The first single released off of the album was "Shit on You", followed by "Purple Pills", an ode to recreational drug use. For radio and television, the censored version "Pills" was heavily rewritten to remove many of the song's references to drugs and sex and was renamed "Purple Hills". While that single was a hit, the album's second single, "Fight Music", was not as successful.

After their debut, D12 took a three-year break from the studio, later regrouping to release their second album, D12 World, in 2004, which featured the popular hit single release "My Band". In April 2006 D12 member (and Eminem's childhood friend) Deshaun "Proof" Holton was killed in a club brawl on 8 Mile Road in Detroit, Michigan, with U.S. military veteran Keith Bender Jr., who also died in the fray. The eruption is suspected to have been due to an argument over a game of pool. Proof was then allegedly shot by the bouncer Mario Etheridge, Bender's cousin. He was taken by private vehicle to St. John Health's Conner Creek Campus, an outpatient emergency treatment site, but pronounced dead on arrival. Eminem and former Detroit Shady Records artist Obie Trice spoke at the funeral. D12 member Bizarre said that Eminem is not featured on his new album Blue Cheese & Coney Island because "he's busy doing his thing".