What is the effect of melatonin on jet lag syndrome? Jet lag desynchronizes the internal sleep-wakefulness cycle with the environmental light/dark cycle. Advance (but not delay) of light onset is known to abolish pineal N-acetyltransferase activity and urine excretion of 6-sulphatoxymelatonin. Measurements of pineal serotonin, the substrate of melatonin biosynthesis; N-acetylserotonin (NAS), the immediate melatonin precursor; and melatonin (high-performance liquid chromatography-fluorimetric method) in the animal (rat) model of jet lag revealed that prolonged delay of darkphase onset disrupted the rhytms in comparable ways as the advance of light-phase onset. Advance of dark phase onset resulted in less severe disturbances of rhythms as compared with the advance of light phase onset. Melatonin, but not NAS, injections at the beginning of a new dark period accelerated recovery of NAS and melatonin, but not serotonin, rhythms. Spontaneously hypertensive rats were more sensitive to advance of light onset and less responsive to melatonin injections than normotensive rats. NAS and methylene blue, an inhibitor of monoamine oxidase A, attenuated light-induced disruption of NAS but not melatonin rhythms. We draw the following conclusions from our data: the beginning of the dark period may be preferable to the beginning of light period as the arrival time on eastward flights; the efficacy of melatonin in alleviating jet lag may be enchanced by administering it before, during and after rapid transition through time zones; and hypertension may exaggerate jet lag syndrome.