This chapter shows that structural and functional brain imaging methods have offered into the neural substrates of affective processes as well as the current and possible future utility of these methods in the evaluation and management of patients with treatment-resistant mood disorders. Neuroanatomic models of the substrates of affective processes were originally derived from non-human animal studies in addition to postmortem and in vivo studies of humans with brain trauma, neurologic, and psychiatric disorders. The chapter reviews brain imaging studies in mood disorders, which in many cases demonstrate disruptions in anterior paralimbic structures and anterior basal ganglia-thalamocortical circuits. Many of these studies involved treatment-resistant patients or patients in tertiary care institutions and thus may be particularly indicative of the neurobiology of treatment-resistant mood disorders. Thus, a useful initial approach to the treatment-resistant mood disorder patient is to reassess whether the disorder is primary or secondary.