For the past half-century, antidepressant development has been dominated by drugs that interfere with monoamine neurotransmitters. Some progress regarding safety and adverse effects is undeniable, and the increasing specificity of most current antidepressants targeting exclusively monoamines accounts for this improvement. Nevertheless, existing antidepressants exhibit limited efficacy and protracted onset of action, and we still do not know whether the pharmacological actions delineated thus far are those that account for the clinical benefits of these drugs in 60%–70% of patients with depression. Severe depression poses a particularly difficult problem, because failure to achieve clinical remission yields the risks of extended illness duration and chronicity (Nemeroff 2007). Elucidation of crucial steps in the mechanism of action of current antidepressants could yield an array of new drug candidates. The alternative route to developing better antidepressants relies on the increasing knowledge of the pathophysiology of depression emerging from clinical research and well-founded hypotheses derived from animal models. Despite huge research efforts by both academic and pharmaceutical industry investigators, none of the many discoveries of mechanisms involved in depression-related behavior has yet been translated into clinical application.