Juelz Santana was born in Harlem, New York to African American and Dominican parents. He began writing rhymes at the age of twelve and was originally signed to Priority Records as one half of the duo called Draft Pick. The group had several shows around New York City while together, including Amateur Night at the Apollo Theatre, where they won two weeks in a row. Some time after this, in 1999, he was introduced to Cam'ron through his cousin Maria Thompson. He impressed Cam'ron with his unique delivery and command of his freestyles and Cam'ron, a seasoned artist, recognized star potential in the teenage Santana. His first rapping appearance can be heard on Camron's remix of "What Means the World to You," which features the artists Ludacris, UGK, and Trina. He is now signed as a solo artist to Diplomat Records/Def Jam Recordings.

In 2003, Santana released an album, From Me to U, under Def Jam Records. In 2005, he released a Billboard's Top Rap Albums and Top R&B/Hip-Hop Albums charts. On March 18, 2008, he announced on BET's 106 & Park that he would collaborate with Lil Waynein his next studio album. Dates have not been confirmed. His next album, "Born to Lose, Built to Win (The Reagan Era)" is slated for summer 2008 release.