The hypothesis that 5-hydroxytryptamine (5-HT) acting through 5-HT_2c receptors is a key factor in the initiation of migraine has been re-evaluated in the light of recent basic and clinical scientific developments. The key findings are that nitric oxide is an important trigger for migraine, that 5-HT_2B/5-HT_2C receptors are present on endothelial cells and trigger nitric oxide release when activated and that supersensitivity of the 5-HT_2B/5-HT_2C receptor is a neurochemical feature predisposing to headache. Taken together the data bring new perspectives to the role of 5-HT acting through 5-HT_2C (or closely similar) receptors in the initiation of migraine.