Hypotheses of antidepressant action which argue that even norepinephrine (NE) uptake inhibitors ultimately work through potentiation of serotonergic function are critically reviewed. Preclinical electrophysiologic data can be interpreted as evidence for enhanced serotonin (5-HT) throughput as a common mechanism of action of all antidepressants. Biochemical data in rats (e.g., microdialysis) and humans (e.g., opposite effects of ECT on 5-HIAA in cerebrospinal fluid), however, suggest that more is involved than simply enhanced 5-HT function when NE uptake inhibition is combined with 5-HT uptake inhibition. The case, however, for noradrenergic effects on 5-HT function is quite strong either with regard to stimulation of alpha 1 receptors on 5-HT cell bodies or alpha 2 heteroreceptors on 5-HT nerve endings. Even the reported ability of pindolol to potentiate the antidepressant effects of 5-HT uptake inhibitors may prove to involve noradrenergic effects and not simply antagonism of 5-HT1A receptors as currently hypothesized. The biochemically specific drugs needed to directly test these concepts are not yet available. On the other hand, compounds which combine noradrenergic and serotonergic effects (e.g., alpha 2 antagonism and 5-HT2 antagonism) that go beyond those of the classic uptake inhibitors are emerging as agents to test the clinical potential of selective manipulation of these interacting neurotransmitter systems.