Approximately 20% of adolescents experience at least one depressive episode by the time they enter their adult years. For most adolescents, depression, although serious, either remits spontaneously or responds to treatment. For a smaller but significant proportion of adolescents, however, depression can be long-lasting and relatively unresponsive to initial treatment. In this article the authors provide an operational definition of treatment-resistant depression, identify factors associated with treatment nonresponse, describe an approach to the management of treatment-resistant depression, and advance suggestions for promising avenues of research.