The current study examined rumination in response to stress as a common vulnerability factor to both depression and substance use problems in adolescence. Specifically, we used a multi-wave longitudinal design to examine whether adolescents who tend to ruminate in response to stress exhibit increases in depressive symptoms and substance misuse following the occurrence of negative events. At time 1, adolescents (n = 161) completed measures assessing depressive symptoms, substance misuse, and the tendency to ruminate in response to stress. Every 6 weeks for the next 18 weeks participants completed measures assessing the occurrence of negative events, depressive symptoms, and substance misuse. Hierarchical linear modeling analyses indicated that adolescents who tend to ruminate in response to stress report greater elevations in depressive symptoms and substance misuse following elevations in negative events than other adolescents. The relationship between rumination, negative events, and substance misuse was moderated by age. Support was not obtained for fluctuations in depressive symptoms as a mediator of the relationship between negative events and substance misuse. Fluctuations in negative affect, however, were found to mediate this relationship.