The role of melatonin in human glucose regulation is poorly understood. Under normal conditions, glucose tolerance is modulated by circadian rhythmicity and sleep, two central nervous system processes which may be influenced by melatonin. In the presence of a constant stimulus (e.g. intravenous glucose infusion), blood glucose levels increase from morning to evening and further increase until the middle of sleep, when a decline towards morning levels is initiated. This 24-h variation is due to coordinated changes in insulin-dependent and non-insulin dependent glucose utilization (e.g. by the brain), in insulin sensitivity and in insulin secretion. Causative roles for the 24-h cortisol rhythm and for sleep-related growth hormone release have been clearly identified. Changes in sympatho-vagal balance at the level of the pancreas could also be implicated but have not been investigated. Melatonin is likely to play an indirect role in the mechanisms underlying glucose regulation via its actions on the suprachiasmatic nucleus and on sleep regulation.