The present study is designed to address the problem of risk behaviors among adolescents, in an effort to promote positive developmental trajectories. Previous studies have resulted in divergent findings pertaining to the predictors of adolescent engagement in risk behaviors. In addition to considering this divergence, the focus of the study is the nature of bidirectional individual ó contextual relationships and their influence on adolescent engagement in risk behaviors. The study tested two models that considered whether parent-adolescent relationship or peer relationship mediated the relation between theory and research-based predictors and the endogenous variable, co-occurring substance use and sexual activity. Participants were 396 demographically diverse multi-problem adolescents from an archived dataset derived from an HIV risk reduction outpatient treatment program for alcohol and other drug use. Participants responded to questions that measured family structure, parent-adolescent relationship quality and communication, religiosity, school connectedness, peer relationship, and engagement in substance use and sexual activity. The study found that the model with peer relationship as the mediator fit the data better than the model with the parent-adolescent relationship mediator, and that the mediated model provided a better fit to the data than direct relations between the exogenous and endogenous variables. The results suggested also that primary caregiver was not a significant predictor of adolescent participation in co-occurring substance use and sexual activity. The present study provides a holistic theoretical and conceptual framework that highlights a constellation of factors determined to contribute significantly to co-occurring substance use and sexual activity, and thereby reshape existing models of risk behavior among adolescents.