In the past two decades, much evidence has accumulated unequivocally demonstrating that child abuse and neglect is associated with a marked increase in risk for major psychiatric disorders (major depression, bipolar disorder, post-traumatic stress disorder [PTSD], substance and alcohol abuse, and others) and medical disorders (cardiovascular disease, diabetes, irritable bowel syndrome, asthma, and others). Moreover, the course of psychiatric disorders in individuals exposed to childhood maltreatment is more severe. Recently, the biological substrates underlying this diathesis to medical and psychiatric morbidity have been studied. This Review summarizes many of the persistent biological alterations associated with childhood maltreatment including changes in neuroendocrine and neurotransmitter systems and pro-inflammatory cytokines in addition to specific alterations in brain areas associated with mood regulation. Finally, I discuss several candidate gene polymorphisms that interact with childhood maltreatment to modulate vulnerability to major depression and PTSD and epigenetic mechanisms thought to transduce environmental stressors into disease vulnerability.