Although the neighborhood microsystem is recognized as an important domain for adolescent development, relative to the family and peer contexts, neighborhood factors have been understudied in relation to adolescent substance abuse. In addition, recent research suggests that risk factors for adolescent substance use may differ for African Americans when compared to Caucasian youth. This study investigated the association between perceived neighborhood disorganization and later substance use, as well as possible mediators of that association, among a community sample of urban African American adolescents. Perceptions of neighborhood disorganization (i.e., violence/safety and drug activity) in grade 7 were associated with increased tobacco, alcohol, and marijuana use in grade 9. For females, this association was mediated by attitudes about drug use and perceptions of drug harmfulness. Findings highlight the importance of neighborhood contextual variables for African American substance use. Implications and directions for future research are presented.