Despite extensive research, the biochemical abnormalities underlying the predisposition to and the pathogenesis of affective disorders remain to be clearly established. Efforts to study norepinephrine (NE) output and function have utilized biochemical assays, neuroendocrine challenge strategies, and measures of peripheral blood cell receptors; the cumulative database points to a dysregulation of the noradrenergic system. Depressed patients (in particular, melancholic, unipolar subjects) excrete disproportionately greater amounts of NE and its major extraneuronal metabolite, normetanephrine, than do controls. Depressed patients also show subsensitive neuroendocrine (growth hormone) and biochemical (inhibition of adenylate cyclase) responses to alpha 2-adrenergic agonists, suggesting that subsensitivity of nerve terminal alpha 2 autoreceptors may underlie the exaggerated plasma NE observed in response to various challenges in affective disorders. Future advances in brain imaging techniques and in the molecular biology of adrenergic receptor-coupled signal transduction systems offer promise for meaningful advances in our understanding of the pathophysiology of affective disorders.