The monoamine hypothesis of depression predicts that the underlying pathophysiologic basis of depression is a depletion in the levels of serotonin, norepinephrine, and/or dopamine in the central nervous system. This hypothesized pathophysiology appears to be supported by the mechanism of action of antidepressants: agents that elevate the levels of these neurotransmitters in the brain have all been shown to be effective in the alleviation of depressive symptoms. However, intensive investigation has failed to find convincing evidence of a primary dysfunction of a specific monoamine system in patients with major depressive disorders. Understanding of the etiology of depression has been hampered by the absence of direct measurements of monoamines in humans. However, the monoamine depletion paradigm, which reproduces the clinical syndrome, allows a more direct method for investigating the role of monoamines. Results from such studies show that antidepressant responses are transiently reversed, with the response being dependent on the class of antidepressant. In contrast, monoamine depletion does not worsen symptoms in depressed patients not taking medication, nor does it cause depression in healthy volunteers with no depressive illness. In conclusion, it is clear that antidepressant agents in current use do indeed require intact monoamine systems for their therapeutic effect. However, some debate remains as to the precise role that a deficiency in monoamine system(s) may play in depression itself.