This article examines the role of adolescent social relationships in fostering the occurrenceand co-occurrence of depression and substance abuse, using two waves of data from acommunity sample of adolescents (N = 900). Multinomial logistic response modelswere 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 adolescentadaptation, contrasts involved four subgroups of adolescents: those high on both depressed moodand substance abuse, those who experience neither problem, those evidencing high levels ofdepressive symptoms only, and those high on substance abuse only. Risk for depressivesymptoms was differentiated by its association with conflict and lack of support in the friendshipdomain. Substance abuse was associated with negative peer pressure, but these youth wereotherwise little different from youths with no problems. Whereas co-occurrence of depressionand substance use was associated with more difficulties in both the family and peerenvironments, the most distinctive risk was that of low family support. Discussion centers on thedevelopmental antecedents of co-occurring problems and family relations duringadolescence.