Ketamine (Ketalar¨) is an anesthetic agent derived from the hallucinogenic drug phencyclidine (PCP). It is a high-affinity antagonist at N-methyl-D-aspartate receptors and also binds to opioid mu and sigma receptors. Ketamine is being intensively investigated as an antidepressant therapy. To date, five short-term controlled studies and other open-label studies in patients with unipolar or bipolar depression have demonstrated that intravenous ketamine is safe and has a rapid and profound short-term effect on depressive symptoms, including suicidal thoughts, even among patients considered treatment-resistant to standard medications or electroconvulsive therapy. Before ketamine can be incorporated into clinical practice, however, its long-term safety and effectiveness need to be evaluated. Although the effectiveness of alternative routes of ketamine administration (i.e., oral, intranasal, or intramuscular) needs to be determined, intravenous ketamine could be conceptualized as a clinic-based procedural therapy for treatment-resistant forms of depression.