Drug development in psychiatry has evolved from a process dependent on chance discovery to one based on rationally targeting specific mechanisms of action believed to be important in the pathophysiology underlying psychiatric syndromes. Antidepressant pharmacotherapy is the first area to have substantially benefited from this evolution. Serotonin selective reuptake inhibitors (SSRIs) were the first class of psychiatric medications developed based on such molecular targeting. Nefazodone is a new antidepressant that combines blockade of the serotonin-2 receptor with serotonin uptake inhibition. Perhaps as a result of this dual action, nefazodone caused fewer complaints of nervousness (e.g., agitation, anxiety), insomnia, and tremors and a higher incidence of confusion, dizziness, and vision disturbance than do other advanced generation antidepressants based on several different ways of assessing the relative incidence of these adverse effects. Reports of sexual dysfunction on nefazodone and bupropion treatment were lower than on treatment with other recently released antidepressants.