Although highly selective antidepressants such as the selective serotonin reuptake inhibitors represent an advance over older drugs with respect to tolerability, they are not more effective than previous agents. Antidepressants that enhance transmission in more than one monoamine system may have greater efficacy than highly selective drugs, while equaling or improving their adverse effect profiles. This article reviews the properties of duloxetine, a potent and balanced inhibitor of norepinephrine and serotonin reuptake. Controlled studies indicate a high degree of efficacy, tolerability, and safety for duloxetine in the treatment of major depressive disorder. In particular, rapid therapeutic onset and high remission rates have been noted. Duloxetine appears to have significant benefit in the treatment of the painful physical symptoms associated with depression. The continued presence of such symptoms may predict relapse. Accordingly, it is hoped that duloxetine therapy may reduce the likelihood of depressive relapse.