There is increasing interest in the hormone melatonin in postoperative and critically ill patients. The roles of melatonin in the regulation of the sleep-wake cycle, resetting of circadian rhythm disturbances and its extensive antioxidant activity have potential applications in these patient groups. The interaction between melatonin and the stresses of surgery and critical illness are explored in the context of circadian rhythms, sleep disorders and delirium. The antioxidant activity is discussed in terms of the reduction of ischaemic reperfusion injury, prevention of multi-organ failure and treatment of sepsis. Unfortunately, there is currently insufficient evidence that exogenous melatonin is effective in preventing or treating postoperative delirium. Similarly, in the critically ill patient, sleep disorders are associated with disrupted melatonin circadian secretion, but there is a paucity of data to support routine exogenous melatonin supplementation. More clinical evidence to confirm the potential benefits of melatonin therapy is required before it can be routinely used in the postoperative or critically ill patient.