Evidence is reviewed indicating that instability in central nervous system handling of 5-hydroxytryptamine may be of primary importance in the pathogenesis of migraine, and that the observed diminution of platelet content and uptake of 5-hydroxytryptamine related to an attack may merely be a reflection of this. The rationale is discussed for selecting mianserin as a potentially effective migraine prophylactic based on: (i) its ability to restore to normal platelet 5-hydroxytryptamine uptake when this is decreased in depression; (ii) its effect on the central nervous system; and particularly (iii) its antiserotonergic activity. A double-blind control trial of mianserin versus placebo in the prophylaxis of migraine is described. There was a significant fall in both frequency and severity of migraine attacks when compared with baseline values in mianserin-treated patients but not in placebo-treated patients. There was no accompanying change on the Beck Depression Inventory. It is concluded that mianserin is an effective migraine prophylactic in some patients. There is no evidence indicating which pharmacological property of mianserin is responsible for this effect.