Background: Behavior genetic methods can help to elucidate gene-environment (G-E) interplay in the development of internalizing (INT) disorders (i.e., major depression and anxiety disorders). To date, however, no study has conducted a comprehensive analysis examining multiple environmental risk factors with the purpose of delineating general mechanisms of G-E influence in the development of INT disorders. Methods: The sample consisted of 1315 male and female twin pairs participating in the age 17 assessment of the Minnesota Twin Family Study. Quantitative G-E interplay models were used to examine how genetic and environmental risk for INT disorders changes as a function of environmental context. Multiple measures and informants were employed to construct composite measures of INT disorders and six environmental risk factors including: stressful life events, mother-child and father-child relationship problems, antisocial and prosocial peer affiliation, and academic achievement and engagement. Results: Significant moderation effects were detected between each environmental risk factor and INT such that in the context of greater environmental adversity, nonshared environmental factors became more important in the etiology of INT symptoms. Conclusion: Our results are consistent with the interpretation that environmental stressors have a causative effect on the emergence of INT disorders. The consistency of our results suggests a general mechanism of environmental influence on INT disorders regardless of the specific form of environmental risk.