A large body of research has identified correlates of risky sexual behavior, with depressive symptoms and marijuana use among the most consistent psychosocial predictors of sexual risk. However, substantially less research has examined the relationship between these risk variables and adolescent risky sexual behavior over time as well as the interaction of these individual-level predictors with family-level variables such as parenting factors. Additionally, most studies have been restricted to one index of risky sexual behavior, have not taken into account the complex role of gender, and have not controlled for several of the factors that independently confer risk for risky sexual behavior. Therefore, the current study investigated the association between depressive symptoms and parameters of parenting on marijuana use, number of sexual partners and condom usage measured 9 months later for both boys and girls. Participants were 9th and 10th grade adolescents (N = 1,145; 57.7% female). We found that depressive symptoms may be a gender-specific risk factor for certain indices of risky sexual behavior. For boys only, marijuana use at Time 2 accounted for the variance in the relationship between depressive symptoms at Time 1 and number of partners at Time 2. Additionally, strictness of family rules at Time 1 was associated with the number of partners with whom girls engaged in sex at Time 2, but only among those with lower levels of depressive symptoms at Time 1. Results from the current investigation speak to the utility of examining the complex, gender-specific pathways to sexual risk in adolescents. Findings suggest that treatment of mental health and substance use problems may have important implications in rates of risky sexual behavior and, conceivably, controlling the high rates of serious individual and public health repercussions.