Major depressive disorder is a debilitating disease that imposes significant social and economic burdens not only on patients but also on society. Although various treatment options are available, treatment-resistant depression is common. Determining the exact prevalence of treatment-resistant depression is difficult because definitions vary, as do definitions of antidepressant response. Operational definitions of antidepressant response, nonresponse, partial response, and remission will be discussed in this article. Pharmacotherapy options for patients with treatment-resistant depression include augmentation, combination, and switching therapies; however, data from controlled clinical trials supporting these therapies are limited. Electroconvulsive therapy and psychotherapy offer additional treatment strategies. New nonpharmacologic therapies are under investigation. Remission is the goal of treatment.