Neither 5-hydroxytryptamine (HT) nor 5-hydroxytryptophan (HTP) induced migraine by intravenous administration in 35 cases. Subcutaneous paratemporal arterial injections of HT in 25 cases failed to produce symptoms of migraine. Increase in endogenous serotonin by means of phenelzine, a monoamine oxidase inhibitor, did not provoke migraine. Peripheral block of serotonin by 2-bromo-lysergic acid diethylamide (BOL) has not provoked migraine. HT and HTP did not produce eeg changes in 35 cases of migraine with normal tracings. Reserpine (2.5 mg intramuscularly) induced typical migraine headache in 9 of 10 patients by a mechanism remaining to be clarified. Phenelzine, a monoamine oxidase inhibitor, given over a short period of time in this series, markedly reduced the frequency and severity of migraine. BOL given over a short period of time in this aeries has markedly reduced the frequency and severity of migraine. HT abolished spontaneous migraine headaches. HTP abolished both spontaneous migraine and reserpine-induced headaches. In 3 instances of spontaneous migraine, the plasma level of HT was not remarkably altered. Possible mechanisms of migraine and the role of serotonin are discussed.