In summary, depressed patients with a history of childhood trauma may have a distinct depression endophenotype characterized by a specific neurobiology and risk genotype that may be responsive to different treatment strategies than depressed patients without childhood adversity. Based on current findings, treatment strategies should be multimodal and include the following: 1. Psychotherapy that addresses a number of domains, such as emotional regulation, cognitive reframing, careful exploration of past traumatic events, attachment, and interpersonal relationships in a safe and trusting therapeutic environment. 2. The therapy should likely be longer term in order to effectively impact those domains. 3. Pharmacotherapy that will be effective in quieting the body’s hyperresponsiveness to stress and reverse epigenetic modifications induced by trauma and stress. 4. Environmental interventions that provide a support network (maternal care, a positive family environment, the support of a close friend) have all been shown to attenuate the impact of childhood abuse. In addition, there is great potential in the identification of genomic biomarkers to help guide us in the identification of traumatized individuals who are susceptible to depression. These indices may also help identify those for whom the immediate provision of treatment may have a preventive effect and may someday guide us in the development of novel pharmacologic approaches.