Major depressive disorder affects tens of millions of people each year. One-third of those affected have depression that is resistant to conventional pharmacologic, psychologic, or somatic treatments. Patients with treatment-resistant depression have few remedies other than electroconvulsive therapy or transcranial magnetic stimulation. Recent research has highlighted the promising antidepressant effects of subanesthetic ketamine infusions. This journal course examines the efficacy of ketamine for treatment-resistant depression. Evidence from 10 systematic reviews and randomized controlled trials suggest that most of the researchers concluded ketamine significantly decreased depression severity ratings at short-term assessment intervals, whereas evidence examining the long-term effects is lacking. Ketamine infusion therapy was generally well tolerated, with minimal untoward effects. Large, randomized controlled trials are needed to discern the longer-term efficacy, tolerance, and dependence profiles of ketamine infusions. Optimal dosing schedules to best prolong the antidepressant effects of ketamine have yet to be determined.