The 31-year-old hip-hop star collaborated with rap icon Eminem, 38, back in 2005 on a track called We Ain't, which featured on Game’s debut studio album The Documentary.
However, Game’s famous feud with Eminem’s protégé 50 Cent has since affected their relationship, and the rapper admits the former shouldn’t be messed with.
"One thing that stuck with me is that Eminem is not to be f**ked with ever in hip-hop, ever," he told Sway on Wednesday's RapFix Live.
"If you notice out of everybody I take a shot at, that's the only person that's untouched. He's in a bubble and you don't even say nothing to Eminem. To anybody that ever does, God bless you. He'll end your career."
Game and 50’s rift began in 2005, with disses being made on both sides. Although they tried to make a truce during a press conference in New York, it didn’t last. Game even claimed to MTV News that late pop icon Michael Jackson had attempted to reunite the warring rappers, to no avail.
Game admits his fighting with 50 has also had an impact on his relationship with hip-hop mogul Dr. Dre, who has helped both him and 50 in their careers in the past. He has tried to remain professional in the light of his various insults.
"It wasn't personal to anybody; I told that to Dre, I've told that to Paul Rosenberg, who manages Em, and the only the person I hadn't spoke to about it was Em and 50," he explained.