Evidence that secondary mood disorders are distinct clinical entities is mounting; and comparisons of mood disorders due to various medical or systemic conditions are only now beginning in earnest. Unlike mood disorders secondary to neurological illness, those secondary to medical conditions show wide variability in their prevalence rates and lack evidence of structural lesions within the central nervous system (CNS) as a pathophysiologic basis for their emergence. The authors selectively review literature published since 1990 concerning mood disorders secondary to four areas of medical illness: endocrine disorders, coronary artery disease, cancer, and end-stage renal disease. Potential pathophysiologic mechanisms for these depressions are examined, these include the role of cytokines in the CNS, subclinical cerebrovascular disease or leukoencephalopathy, altered platelet function, and dysregulation of CNS functions. Recent advances are dispelling old constructs regarding depressiosn in medical illness, but longitudinal studies of specific diseases are needed together with further work on the pathophysiology of these mood disorders.