Depressive disorders are highly prevalent and are a leading cause of disability, morbidity, and mortality worldwide; however, they often remain undertreated or untreated. This article provides a broad overview of the many strategies for treating depression. More than 24 antidepressant medications and depression-focused psychotherapies are available as first-choice options for treating depression. When patients have not had a satisfactory treatment response, the 2 main strategies are switching to an alternative antidepressant therapy or adding a second antidepressant therapy. A large number of medication combinations have been reported in the literature, and some have been shown to be effective in controlled studies. Nonstandard alternatives to conventional antidepressant treatments include exercise, light therapy, sleep deprivation, and various complementary and alternative therapies. For more chronic and refractory forms of depression, various neuromodulation therapies are available or are being investigated. Because depressive disorders are common in primary care and other medical settings, medical practitioners should be aware of the therapeutic armamentarium available for treating depression.