The World Health Organization lists ketamine as essential medicine. Ketamine exerts multiple pharmacological effects in versatile indications. Although it is sometimes abused, medical therapy must not be confused with prolonged, high-dose abuse. For people living in resource-limited settings, its importance as an analgesic and anesthetic is immense. There is worldwide evidence indicating improved analgesia, sleep, mood, rehabilitation, and subjective quality of recovery with adjunctive use of racemic and especially esketamine in perioperative multimodal regimens. Ketamine may reduce neurocognitive dysfunction. It is part of periprocedural and intensive care sedation and analgesia, and explored for approaches to chronic conditions, such as disorders of consciousness or inflammatory syndromes. Racemic and esketamine have been established as fast-acting, effective antidepressants in major and treatment-resistant depression and suicidal ideation. However, ketamine can cause psychoactive events and medical problems, especially with long-term use. In general, the trials exhibit significant heterogeneity, with sometimes inconsistent results. Because ketamine acts context- and dose-dependent, its use must be individualized and situation adapted. In infants and very young children, high doses of ketamine should be avoided, especially as negative effects on neurological development are discussed. To optimize ketamine therapy, high-quality research with a focus on the most effective administration paradigms is needed.