Depression in adolescents has become a major social issue and, in most cases, leads to permanent functional impairment in adulthood. Since then, the discipline has successfully overcome the naive nature versus nurture controversy and embraced dynamic models of integration. This review contributes to a developmental-transactional model, which assumes that depressive outcomes are a result of the interaction of diffuse genetic vulnerabilities and powerful interpersonal stressors. In this case, genetic predisposition creates a risk gradient of probability, which often is manifested as increased sensitivity to the environment, especially the relationship landscapes of family and peers. Genetic factors can affect reactivity to adversity and determine the stressors people face in a systematic manner through gene-environment correlation and interaction mechanisms. A dual-pronged intervention approach is thus needed: to decrease the modifiable social risks and at the same time increase the environmental buffers to reduce the inherent biological vulnerability.