Depression is a relatively common diagnosis in children and adolescents, and is associated with significant morbidity and suicidality in this population. Evidence-based treatment of the acute illness is imperative to try to prevent the development of treatment-resistant depression or other complications. In situations where response to acute treatment is inadequate, clinicians should first consider factors that may influence outcome, such as psychiatric or medical comorbidities, psychosocial stressors, and treatment noncompliance. Selective serotonin reuptake inhibitors (SSRIs) are the first-line treatment for depression in children and adolescents. For treatment-resistant depression, a switch to an alternate SSRI is recommended before trials of other antidepressants. Psychotherapy, such as cognitive behavioral therapy or interpersonal therapy, may improve treatment response. More research is needed examining medication augmentation strategies for treatment-resistant depression in children and adolescents.