The goal of antidepressant drug therapy should be an optimal treatment outcome, which is the absence of significant depressive symptoms, along with a complete recovery of psychosocial function. This kind of outcome is referred to as full remission. With any first-choice antidepressant medication, only approximately 50% of patients will have a significant treatment response, usually defined as a 50% or greater decrease in depressive symptoms. Of those patients who respond to treatment, only approximately one half to one third attain full remission. Thus, a significant proportion of patients with depression are left with residual or persistent symptoms, despite apparently adequate antidepressant therapy (Trivedi et al., 2006a). Treatment-resistant depression (TRD) is therefore defined as the failure to achieve full remission with an antidepressant drug used at an adequate dosage for an adequate duration. In this article, I will discuss some fundamental pharmacotherapy strategies for TRD.