Now That's What I Call Music! 21 was released on April 4, 2006. The album is the twenty-first edition of the (U.S.) Now series. It peaked at number 1, 3 and 4 on the Billboard 200 and has been certified 2x Platinum by the RIAA. The compilation includes three songs which reached the Billboard Hot 100: "Don't Forget About Us", "Grillz" & "Run It!".
The cover is inspired by the NOW 62 UK cover released in 2005.