Though recent evidence indicates that rates of illicit drug use among African American women are now higher than the national average, little is known about the etiology of substance use in this population. In addition, the effects of racism and other cultural factors are understudied and may be unique amongst African American women. This cross-sectional study explores risk and protective factors for drug use among 204 African American women. More specifically, associations between racism experiences and drug use are investigated in the context of potential moderating influences (i.e., psychosocial resources, social safety net variables, and cultural identity and practices). Findings suggest that racism is associated with drug use, but that its effects diminish with age. In addition, results suggest that psychosocial resources, social safety net factors and culturally specific factors like ethnic community membership and engagement in cultural practices afford African American women some protection against the detrimental effects of racism.