Studies are reported of the variation of melatonin in serum, plasma urine and cerebrospinal fluid in normal subjects and in patients with various diseases. The diurnal variation of plasma and urine melatonin found in healthy controls on a regular dark-sleep pattern persisted when the subjects slept in light. The effect of sleep deprivation and of rapid light exposure at night is reported. There was a correlation between melatonin in morning urine and plasma at 2 a.m. Four hours of extended darkness in the morning as well as a 9-hour shift of sleep and activity cycles following travel affected the melatonin rhythm. The night increase in plasma melatonin preceeded both the cortisol and prolactin rise. A single oral dose of 4.3 X 10(5) nmol of melatonin given to a 44-year-old healthy male gave a peak plasma value of 624 nmol/l after 30 min. Plasma melatonin was not affected by electroconvulsive therapy, TRH-injection, L-Dopa or bromoergocryptine orally. Patients with alcoholism, migraine, postoperative pinealoma, panhypopituitarism, hereditary dystonia and schizophrenics on propranolol exhibited a decreased amplitude of their diurnal rhythm of melatonin. Two patients with pituitary tumors had occasional high levels of plasma melatonin. The change in melatonin secretion in human is apparently controlled by a mechanism which is at least party influenced by environmental lighting conditions, drugs and different disease states.