Although the pathophysiology of depression is not fully understood in either primary depression (i.e., no known neuropathology related to depression) or secondary depression (i.e., neuropathologic disorder that leads to depression), a number of studies have begun to identify aspects of the pathophysiology of both primary and secondary depression. This article reviews the findings of studies examining the pathophysiology of depression following stroke, Parkinson's disease, or Huntington's disease and compares them to findings in primary depression. Studies examining glucose metabolic rates or blood flow changes in regional brain areas found that stroke, Parkinson's disease, and Huntington's disease, as well as primary depression, were all associated with decreased activity or brain lesions in the orbital frontal cortex and basal ganglia. There were also abnormalities noted in the basal temporal lobes, cingulate cortex, and thalamus in some but not all disorders. Studies in stroke have also noted depletions of serotonin receptors in left temporal cortex associated with depression. These findings are consistent with the hypothesis that the pathophysiology of secondary and primary depression involves the dysfunction of one or more of the cortical-basal ganglia-thalamic neuronal loops. This dysfunction may be mediated by decreased serotonin release. These studies may ultimately lead to more focused and specific treatments.