The mechanism of action of the antidepressants was reviewed through the summer of 1995. Antagonism of monoamine transport is the primary cellular action associated with many antidepressant medications. However, an increased synaptic concentration of monoamines is not the actual mechanism of antidepressant effects as suggested by the time lapse between treatment initiation and the onset of clinical antidepressant response. Chronic administration of all antidepressants increases the efficiency of 5-HT transmission in the synapse, albeit by different mechanisms. Serotonin transporter antagonists enhance serotonergic neurotransmission by decreasing the functional activity of the 5-HT 1A and 5-HT 1B autoreceptors. Tricyclic antidepressants and electroconvulsive therapy enhance 5-HT neurotransmission by increasing the responsiveness of postsynaptic 5-HT receptors. Monoamine oxidase inhibitors and the 5-HT 1A agonists increase serotonergic function by desensitizing the somatodendritic autoreceptor; the terminal 5-HT autoreceptor is not affected by these agents. Evidence for both enhanced and diminished noradrenergic transmission following antidepressant treatment exists, although the evidence more strongly supports decreased noradrenergic transmission. Ongoing investigations into intracellular adaptations (e.g., steroid receptors, growth factors, etc.) during chronic antidepressant administration offer the promise of furthering our understanding of the mechanism of action of antidepressants. Depression and