We examined the prospective relations between a cultural risk factor, perceived racial discrimination (PRD), and subsequent negative affect and health behavior (smoking) in a panel of 889 African American children (part of the Family and Community Health Study). Cultural moderators (protective factors) of these relations were also examined. PRD was assessed six times from ages 10.5 (Wave 1) to 24.5 (Wave 6), and negative affect (anger and depressive symptoms) was assessed at Wave 2 (age 12.5) and Wave 6 (age 24.5). Results indicated that Wave 1 PRD predicted Wave 6 smoking, controlling for multiple factors related to smoking and/or PRD, including smoking at age 15.5. Structural equation models indicated that these relations between Wave 1 PRD and smoking were mediated by both early and later negative affect. The models also indicated that Wave 1 PRD had a direct impact on Wave 6 anger (assessed 14 years later), controlling for the effects of PRD on early affect. Cultural socialization was associated with lower rates of adolescent smoking, and it buffered the relation between PRD and Wave 6 anger. The impact of early PRD experiences along with suggestions for culturally informed interventions and preventive interventions that might buffer against early PRD effects are discussed.