The past decades of research on predictors of depression have frequently emphasized interactive diathesis-stress questions: What kinds of vulnerabilities under stressful circumstances increase risk of developing depression? This study addresses 3 theoretically important gaps in our knowledge regarding diathesis-stress models of depression: the role of temperament (neuroticism), interactive versus additive effects of neuroticism-stress relationships, and effects of stressor characteristics (acute vs. chronic, major vs. minor events, interpersonal vs. noninterpersonal content). We addressed these gaps in the prediction of major depressive episodes (MDEs) in a sample of high schoolers (n = 559) oversampled for high neuroticism and assessed for presence of MDEs annually for 5 years. Survival analyses provided relatively consistent support for the main effects of the broad vulnerability factor of the general neuroticism factor, acute stressors, and chronic stressors in the prediction of MDEs. In contrast, the majority of our analyses failed to support interactive neuroticism-stress accounts of MDE risk. Integrating our results with the extant literature reinforces the notion that both the general neuroticism factor and stress prospectively predict depressive disorders and highlight that their main effects are significantly larger than their interaction. (PsycInfo Database Record (c) 2020 APA, all rights reserved).