This study sought to identify factors that forecast sexual risk and alcohol or other substance use patterns among 411 rural African American males as they transitioned from middle childhood to late adolescence. In addition, an exploration was undertaken to examine the contribution of both risk and protective factors in distinguishing rural African American males at highest risk for engaging in risky sexual behavior and elevated substance use from those with relatively low risk of engaging in these behaviors. Findings revealed that exposure to negative life events during middle childhood has prognostic significance for rural African American males' susceptibility to engaging in HIV-related risk behaviors as they transition into adolescence and young adulthood. High-risk engaging males had significantly higher means on susceptibility to risk and marginally significantly higher means on substance-using peer affiliation. High-risk rural African American males also reported lower means on involved-vigilant parent than the normative group (low-risk group). However, economic hardship, family stress, parental psychological functioning, and harsh and inconsistent parenting did not emerge as significant predictors of high- or low-risk group membership. The implication for future research and preventive interventions is discussed.