This longitudinal study investigated the stress autonomy, stress sensitization, and depression vulnerability hypotheses in adolescents across 6 years (i.e., Grades 6 through 12). Participants were 240 children (Time 1 mean age = 11.86, SD = 0.57) who varied in risk for depression on the basis of their mother's history of mood disorders. All analyses were conducted as multilevel models to account for nesting in the data. Results were consistent with the stress sensitization hypothesis. The within-subject relation of stress levels to depressive symptoms strengthened with increasing numbers of prior depressive episodes. In addition, evidence consistent with the vulnerability hypothesis was found. The relation of stress levels to depressive symptoms was stronger for adolescents who were at risk for depression on the basis of maternal depression history and for those who had experienced more depressive episodes through Grade 12. These findings suggest that onsets of depression in adolescents may be predicted by both relatively stable and dynamic transactions between stressful life events and vulnerabilities such as maternal depression and youths' own history of depressive episodes.