When antidepressant therapy fails to ameliorate the cardinal features of depression--e.g., sleep disturbance, appetite disturbance, suicidality--the clinician must seek an alternate treatment strategy. Treatment nonresponse is usually defined as persistence of depression after 6 weeks of adequate doses as shown by plasma concentrations of antidepressant medication. After the clinician has reassessed the patient and, in particular, the diagnosis of major depression, two major options are available: (1) taper the current antidepressant and initiate a trial of an unrelated antidepressant or (2) potentiate the antidepressant effects of the current antidepressant and initiate a trial of an unrelated antidepressant or (2) potentiate the antidepressant effects of the current antidepressant with either thyroid hormone, usually T3, or lithium. This paper describes in detail the usefulness of these two adjuncts in potentiating the effects of antidepressants and in converting antidepressant medication nonresponders to responders. Other augmentation strategies are also briefly described, including the concurrent use of two antidepressants from different drug classes.