A substantial proportion of patients suffering from major depression experience insufficient clinical response, despite appropriate treatment. Switching to a different monotherapy antidepressant medication is the preferred option for many patients and clinicians. The possible advantages of switching to a different monotherapy, as compared with adding a second agent (i.e., augmenting or combining), include reduced medication costs, fewer drug interactions, better adherence, and less patient burden over time. Response rates for switching, are based largely on open trials, which reveal a response rate of approximately 50%. These response rates are comparable to the response rates reported with augmentation or combination, again established largely by noncomparative open trials. This review article summarizes clinical considerations and available evidence regarding switching antidepressants in the treatment of major depression. Practical issues, such as when to consider switching and how to switch from one medication to another, are addressed.