Several hypotheses regarding the physiopathology of major depression exist. Attention has been focused on cerebral monoaminergic systems, the dysfunction of which is thought to underlie various aspects of depressive symptomatology. There is extensive literature describing the involvement of serotonergic and dopaminergic systems in the mechanism of action of antidepressant drugs. However, a unitary analysis of the data in terms of interaction between different monoaminergic systems is still lacking. In this article, studies reporting the biochemical, behavioral, and clinical effects of tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs), selective blockers of presynaptic dopamine (DA) receptors, and antagonists of serotonin-2 (5-hydroxytryptamine-2 [5-HT2]) receptors were reviewed. Analysis of the current literature indicates that long-term treatment with antidepressants causes adaptive changes of the serotonergic and dopaminergic systems. In particular, long-term administration of TCAs enhances the responsiveness of postsynaptic serotonin receptors to iontophoretically applied serotonin and potentiates the behavioral responses to both direct and indirect dopaminergic agonists. Repeated administration of SSRIs and MAOIs increases serotonergic transmission by desensitizing the inhibitory 5-HT1A somatodendritic and terminal 5-HT1B/1D autoreceptors. Selective blockers of DA autoreceptors exert their antidepressant effect by enhancing DA release. A similar mechanism of action could be hypothesized for 5-HT2 receptor antagonists. There is general agreement that the clinical effect of antidepressant drugs, which becomes evident only after long-term treatment, is caused by their ability to induce adaptive changes of the monoaminergic systems. Increases in both serotonergic and dopaminergic function have been consistently found after long-term treatment with various classes of antidepressant drugs. Recent studies have focused on the functional interaction between the serotonergic and dopaminergic systems to explain the mechanism of the antidepressant action of SSRIs and 5-HT2 antagonists.