Depression is an important predictor of adverse medical outcomes via alterations in autonomic, endocrine, immune, hemostatic, and treatment adherence mechanisms. Depression likely influences each of these processes through its effects on the brain. The purpose of this chapter is to selectively review brain imaging findings in depression and interpret these results in the context of how the brain functions during normative emotion processing. Our review of the neuroimaging literature indicates that depression is associated with alterations in the structure and function of particular nodes of a widely distributed cortico-limbic network that is involved in emotion processing and regulation. Taken together, this evidence supports the notion that brain imaging can advance the behavioral medicine research agenda by contributing to the delineation of mechanisms that mediate established relationships between psychosocial variables on the one hand and medical outcome on the other. To develop a comprehensive neurobiological model of depression and its effects on disease, a research strategy that includes assessment of psychosocial, brain, peripheral mediators, and end-organ variables within the same individuals should be pursued. This chapter provides a review of the neuroimaging evidence on which such a research strategy may be based.