Research in molecular genetics has generally focused on genome-wide association studies (GWAS) and exploratory candidate gene and candidate gene-environment (G × E) studies. In this article it is proposed that hypothesis-driven and biologically informed research provides a complementary approach to GWAS to advance pressing research questions about G × E relations that are of public health relevance. Prior research studies and developmental and evolutionary theory were used to guide hypothesis testing of G × E relationships in this study. The study investigated whether the oxytocin polymorphism, rs53576, moderated the relationship between parental divorce during adolescence and depression symptoms in young adulthood. Oxytocin is a neuropeptide that has been related to the regulation of complex social cognition and behaviors such as empathy, attachment, and nurturance. We hypothesized that the GG polymorphism would be associated with more depressive symptoms following parental divorce, and that this effect would be stronger in females than males. The sample consisted of 340 individuals who participated in a longitudinal study with data used both from adolescence and young adulthood. Findings using prospective follow-up and autoregressive change models supported the hypothesized relationships. Young adult females who had experienced parental divorce during adolescence and had the GG oxytocin genotype reported almost twice as many depressive symptoms relative to young adult females who also experienced parental divorce during adolescence but had the AA or AG genotype. This pattern was not indicated among males. Findings were discussed with regard to how molecular genetic factors in combination with environmental stressors, such parental divorce, framed within a developmental framework may facilitate the future study of G × E relationships in the parental divorce-child adjustment literature and contribute to a prevention science perspective.