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His debut studio album, Get Rich or Die Tryin' (2003), was released to critical acclaim and commercial success. Peaking atop the Billboard200, it spawned the Billboard Hot 100-number singles "In da Club" and "21 Questions" (featuring Nate Dogg). It received nonuple platinum certification by the Recording Industry Association of America (RIAA). That same year, he launched the record label G-Unit Records, the namesake of a hip-hop group he formed two years prior; the label's initial signees were its members, fellow East Coast rappers Lloyd Banks and Tony Yayo. His second album, The Massacre (2005), was met with similar success and supported by his third number-one single, "Candy Shop" (featuring Olivia). He adopted a lighter, further commercially oriented approach for his third and fourth albums, Curtis (2007) and Before I Self Destruct (2009)—both were met with critical and commercial declines—and aimed for a return to his roots with his fifth album, Animal Ambition (2014), which was met with mixed reviews. He has since focused on his career in television and media, having executive-produced and starred in the television series Power (2014–2020), as well as its numerous spin-offs under his company G-Unit Films and Television Inc.

Jackson has sold over 30 million albums worldwide and earned several accolades, including a Grammy Award, a Primetime Emmy Award, thirteen Billboard Music Awards, six World Music Awards, three American Music Awards and four BET Awards. In his acting career, Jackson first starred in the semi-autobiographical film Get Rich or Die Tryin' (2005), which received critical panning. He was also cast in the war film Home of the Brave (2006) and the crime thriller Righteous Kill (2008). Billboard ranked Jackson as 17th on their "50 Greatest Rappers" list in 2023. and named him the sixth top artist of the 2000s decade. Rolling Stone ranked Get Rich or Die Tryin' and "In da Club" in its lists of the "100 Best Albums of the 2000s" and "100 Best Songs of the 2000s" at numbers 37 and 13, respectively.