Response to antidepressants is interindividually variable. It has been suggested that this variability is a direct consequence of etiological heterogeneity. Therefore, the same genes, environments, and gene–environment interactions implicated in different etiological pathways to depression may also predict response to treatment. This article reviews the evidence relevant to this hypothesis by first outlining the roles of genes, environments, and gene–environment interplay in the etiology of depression, and then considering the same factors in treatment response. Environmental exposures, such as childhood maltreatment, are potent predictors of both depression and treatment response. Although alone genetic factors have failed to consistently predict either phenotype, several polymorphisms have been shown to moderate the effects of environmental adversity on the development of depression and treatment response. These findings suggest that the dissection of etiological pathways to depression may provide the key to understanding and predicting response to antidepressants.