Melatonin (MLT) is a methoxyindole secreted principally by the pineal gland. It is synthesized at night under normal environmental conditions. The endogenous rhythm of secretion is generated by the suprachiasmatic nuclei and entrained by the light/dark cycle. Light is able to both suppress or entrain MLT production on light schedule. The nyctohemeral rhythm of this hormone can be determined by repeated measurement of plasma or saliva MLT or urine sulfatoxy-MLT, the main hepatic metabolite. MLT can be considered as the output (the hand) of the endogenous clock. Since the regulating system follows a central and sympathetic nervous pathway, an abnormality at any level could unspecifically modify the MLT secretion, especially in patients with sympathalgia or dysautonomia. MLT plays the role of an endogenous zeitgeber on core temperature or sleep-wake cycle. Exogenous MLT is able to influence the endogenous secretion of the hormone according to a phase-response curve. There are practical implications for this property in situations when biological rhythms are disturbed (jet-lag syndrome, delayed sleep phase syndrome, insomnia in blind people, shift-work, insomnia in elderly people). Improvement of pharmaceutical forms (controlled release preparations) or development of MLT analogs could lead to decisive progress.