A burgeoning literature has accumulated over the past three decades implicating alterations in central nervous system (CNS) serotonergic neurotransmission both in the pathophysiology of depression and in the mechanism and action of antidepressant drug treatment. Specifically, studies have revealed (1) decreases in brain concentrations of serotonin and decreases in cerebrospinal fluid (CSF) concentrations of 5-hydroxyindoleacetic acid (5-HIAA) in a sizeable subgroup of depressed patients; (2) alterations in both presynaptic and postsynaptic CNS serotonergic receptors in depressed patients; (3) alterations in putative peripheral markers of CNS serotonergic function such as platelet serotonin uptake, platelet [3H]imipramine or [3H]paroxetine binding, platelet 5-HT2 receptor density, and whole blood serotonin content in depressed patients; (4) that virtually all known antidepressant agents, regardless of their receptor-specific properties, have been shown to increase the efficacy of CNS serotonergic neurotransmission; (5) that in patients treated with antidepressants who exhibit a remission, rapid depletion of serotonin results in a prompt clinical relapse; and (6) that all known serotonin re-uptake blockers thus far studied have been demonstrated to be clinically effective antidepressant medications. The recent identification and cloning of multiple serotonergic receptor subtypes and the identification and cloning of the serotonin transporter offer further promise for elucidating the role of CNS serotonergic neurons in the pathogenesis of depression and, moreover, for the development of innovative treatment strategies for this disorder.