This article examines the role of adolescent social relationships in fostering the occurrence and co-occurrence of depression and substance abuse, using two waves of data from a community sample of adolescents (N = 900). Multinomial logistic response models were estimated to identify the extent to which risk and protective features of youths' family and peer relations were differentially linked with depressive symptoms, substance abuse, and their co-occurrence. Taking a within-person, configurational approach to adolescent adaptation, contrasts involved four subgroups of adolescents: those high on both depressed mood and substance abuse, those who experience neither problem, those evidencing high levels of depressive symptoms only, and those high on substance abuse only. Risk for depressive symptoms was differentiated by its association with conflict and lack of support in the friendship domain. Substance abuse was associated with negative peer pressure, but these youth were otherwise little different from youths with no problems. Whereas co-occurrence of depression and substance use was associated with more difficulties in both the family and peer environments, the most distinctive risk was that of low family support. Discussion centers on the developmental antecedents of co-occurring problems and family relations during adolescence.