The treatment of depressive episodes remains complicated by the long latency of antidepressant efficacy, insufficient response, and high risk of suicide. Ketamine and esketamine have been proposed as fast-acting substances able to overcome these impediments. Since the first randomized controlled trial in the year 2000, numerous studies have explored the antidepressant efficacy of ketamine and esketamine. Clear evidence has emerged that a single infusion exerts a significant antidepressant and antisuicidal effect in both unipolar and bipolar depression. A few studies suggest that antidepressant response can be improved and maintained by repeated administration. Although intravenous application has been most common, subcutaneous, intramuscular, and intranasal application has also been successful. There is some evidence that ketamine may accelerate the response to electroconvulsive therapy without improving the overall response rate. The precise position of ketamine and esketamine within treatment algorithms have yet to be defined, and issues surrounding potential toxicity need to be resolved.