Oral levomilnacipran extended-release (ER) [Fetzima™], the more active enantiomer of milnacipran, is the most recent serotonin norepinephrine reuptake inhibitor to be approved in the USA for the treatment of adults with major depressive disorder (MDD). MDD is characterized by depression and impairment of cognitive, social and work functioning. Once-daily levomilnacipran ER 40-120 mg was an effective and generally well-tolerated treatment in adults with MDD participating in 8-week phase III trials and a 1-year extension study. After 8 weeks, levomilnacipran ER treatment was associated with significantly greater and clinically meaningful improvements in depressive symptoms than placebo treatment and, in general, higher Montgomery-Asberg Depression Rating Scale responder rates and greater improvements in functional outcomes than placebo. The efficacy of levomilnacipran ER was maintained during the extension study, with no new safety signals detected; ongoing postmarketing evidence should more fully define the long-term safety of levomilnacipran ER. In the absence of head-to-head clinical trials, the relative position of levomilnacipran ER to that of other antidepressants remains to be determined. In the meantime, it is a useful addition to pharmacological options for the treatment of adult patients with MDD. This article summarizes the clinical use of oral levomilnacipran ER in adults with MDD, and briefly reviews the pharmacological properties of levomilnacipran.