With treatment to remission as the gold standard for depression treatment, there is considerable reassessment of treatment approaches with the view to finding and employing agents capable of rapidly eliminating all symptoms and returning patients to normalcy. The mechanisms of action intrinsic to different classes of antidepressants are at the center of this review. The selective serotonin reuptake inhibitors (SSRIs), the most commonly prescribed antidepressants, have a single-action mechanism involved in modulating the reuptake of the neurotransmitter serotonin. The selectivity of the SSRIs renders them safer and more tolerable than the earlier multi-acting monoamine oxidase inhibitors (MAOIs) and the tricyclic antidepressants (TCAs). However, because serotonin is not the only neurotransmitter implicated in the pathophysiology of depression, the selectivity that bestows safety to SSRIs may limit somewhat the antidepressant effect in some patients. A newer class of dual-action antidepressants acts by inhibiting the reuptake of both serotonin and norepinephrine. These serotonin-norepinephrine reuptake inhibitors (SNRIs) have improved side effect profiles compared with the earlier multi-action antidepressants, compare favorably with the SSRIs on safety and tolerability, and reduce depression and its associated symptoms with greater rapidity. This review compares the neurobiology of single- and dual-action mechanisms. © Copyright 2004 Physicians Postgraduate Press, Inc.