Desvenlafaxine (DVS) is a serotonin-norepinephrine reuptake inhibitor (SNRI) with a different pharmacokinetic and pharmacodynamic profile to venlafaxine. It was approved in February 2008 by the United States Food and Drug Administration for the treatment of major depressive disorder (MDD) based on a number of randomized, placebo-controlled clinical trials demonstrating efficacy and safety for patients with MDD. Current evidence indicates that DVS has proven efficacy, acceptable safety and tolerability profiles, convenient once-daily dosing and minimal impact on cytochrome P450 enzyme system and adverse event-prone neuroreceptors. As with all monoamine-based antidepressants, DVS has mixed efficacy results from individual studies, unestablished dosing strategies and limited long-term data, and comparative efficacy/safety with other existing antidepressants should be further investigated. Preliminary evidence also suggests the clinical usefulness of DVS in the treatment of vasomotor symptoms of menopause, anxiety symptoms and painful physical symptoms, although only MDD is the approved indication.