The current study examined whether social status and social integration, two related but distinct indicators of an adolescent's standing within a peer network, mediate the association between risky symptoms (depressive symptoms and deviant behavior) and substance use across adolescence. The sample of 6,776 adolescents participated in up to seven waves of data collection spanning 6th to 12th grades. Scores indexing social status and integration were derived from a social network analysis of six schools and subsequent psychometric modeling. Results of latent growth models showed that social integration and status mediated the relation between risky symptoms and substance use and that risky symptoms mediated the relation between social standing and substance use during the high school transition. Before this transition, pathways involving deviant behavior led to high social integration and status and in turn to substance use. After this transition, both deviant behavior and depressive symptoms led to low social integration and status and in turn greater substance use. These findings suggest that the high school transition is a risky time for substance use related to the interplay of increases in depressive symptoms and deviant behavior on the one hand and decreases in social status and integration on the other.