A significant proportion of patients with MDD are treatment resistant or only partial responders to adequate therapy with a single agent. In this situation, one must consider augmentation with another agent. Lithium and thyroid augmentation have been investigated for many years. In a meta-analysis of double-blind studies involving augmentation with lithium or placebo after nonresponse to conventional antidepressants, lithium augmentation was concluded to be the first-line therapy for depressed patients who failed to respond to monotherapy. One important study reported no significant difference in response rates between T3 and lithium as augmentation agents in patients who had failed to respond to TCAs. Very few controlled, double-blind trials show consistently positive results for the other augmentation strategies, although some open-labeled trials and case reports are promising. Additional placebo-controlled, double-blind studies are needed to assess the efficacy and tolerability of all of these agents, especially in combination with the newer classes of antidepressants.