Major depressive disorder (MDD) is one of the most common psychiatric disorders of childhood and adolescence, but because of symptom variation from the adult criteria, it is often unrecognized and untreated. Symptom severity predicts the initial mode of treatment ranging from psychotherapy to medications to combination treatment. Several studies have assessed the efficacy of treatment in children and adolescents, and others have evaluated the risk of developing adverse effects and/or new or worsening suicidal thoughts and behaviors. Optimal treatment often includes a combination of therapy and antidepressant medication. The most studied combination includes fluoxetine with cognitive behavioral therapy. Once symptom remission is obtained, treatment should be continued for 6 to 12 months before a slow taper is initiated. Although most children and adolescents recover from their first depressive episode, a large number will continue to present with MDD in adulthood. Untreated depression in children and adolescents may increase the risk of substance abuse; poor work, academic, and social functioning; and risk of suicidal behaviors.