Administration of exogenous melatonin in surgical and critical care patients has been investigated for various clinical purposes. Studies have demonstrated that melatonin can be used for treatment of preoperative anxiety. The analgesic effect of melatonin is well documented in experimental studies, but still needs to be established further in human clinical studies. The sleep-regulating effects of melatonin in surgical and critical care patients remain unclear. Melatonin has been shown to reduce emergence delirium in the early postoperative period, but no evidence exists in relation to postoperative and intensive care delirium. Limited evidence exists with respect to reduction of oxidative stress in surgical patients. Melatonin has been shown to improve outcome in experimental sepsis models, but still needs to be documented further in human clinical studies. Mechanisms of actions need to be clarified and most importantly dose-response relationships should to be established within the specific procedures and indications. Finally, paramount issues remain in relation to administration form, dosage, timing of administration, and pharmacokinetics of melatonin in surgical and critical care patients.