Major depressive disorder (MDD) is a highly recurrent condition associated with a substantial burden of disease. Antidepressants alone or in combination with psychotherapy are the mainstay of treatment. Evidence demonstrates that antidepressant agents are significantly more efficacious than placebo in treating MDD, and antidepressants of different types have similar efficacies. However, not all patients respond to initial pharmacological treatment, suggesting the need for antidepressants with different mechanisms of action. Bupropion is a second-generation antidepressant, with a mechanism of action different from most antidepressants, in that it is a dopamine and norepinephrine reuptake inhibitor. Bupropion has demonstrated efficacy in the treatment of MDD, measured by Hamilton depression rating scale total and clinical global impressions severity and improvement scores, the proportion of responders, the proportion of patients in remission of disease, the prevention of relapse and beneficial effect on a range of health-related quality of life measures. With an efficacy that is at least similar to most other common antidepressants, including selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors and other second-generation drugs, bupropion has a favourable acceptability and tolerability profile. In particular, it has a minimal effect on sexual function, comparable or lower rates of somnolence than placebo, and is associated with lower rates of weight gain and sedation than some other commonly used antidepressants. Combination therapy of bupropion with other second-generation antidepressants has been shown to improve outcomes in patients failing antidepressant monotherapy. Bupropion is approved for the treatment of MDD in the USA, Canada and many countries in Europe, and current evidence-based guidelines reinforce its place as an efficacious and well-tolerated treatment option in the pharmacological management of MDD.