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Treatment-resistant depression (TRD) in adolescents is prevalent and impairing. We here review the definition, prevalence, clinical significance, risk factors, and management of TRD in adolescents. Risk factors associated with TRD include characteristics of depression (severity, level of hopelessness, and suicidal ideation), psychiatric and medical comorbidities, environmental factors (family conflict, maternal depression, and history of abuse), and pharmacokinetics and other biomarkers. Management options include review of the adequacy of the initial treatment, re-assessment for the above-noted factors that might predispose to treatment resistance, switching antidepressants, and augmentation with medication or psychotherapy. Other modalities, such as electroconvulsive therapy, vagal nerve stimulation, and repetitive transcranial magnetic stimulation, are also reviewed. Depression and Anxiety, 2011. © 2011 Wiley Periodicals, Inc.