A theory of migraine etiology should explain clinical features, biochemical correlates, and actions of effective therapies. Prostaglandin El (PGE1) involvement in migraine has been investigated, but the findings did not fulfill the above criteria. In the present study, low concentrations of PGE1 potentiated vasoconstriction, and increased PGE1 concentrations produced vasodilatation. Postaglandin synthesis in blood vessel walls was stimulated by prolactin, serotonin and angiotensin, explaining the assocation of migraine with sleep, stress, fluid and electrolyte retention, renal disease and dietary precipitating factors. Finally it was shown that propranolol, amitriptyline, caffeine and other drugs are prostaglandin (PG) antagonists, probably by virtue of membrane stabilizing properties. All drugs effective in migraine therapy oppose PG synthesis or antagonize its action. The understanding of prostaglandins physiology permits a more rational approach to migraine therapy than has been possible in the past.