Theories of migraine pathophysiology have evolved from the realms of the supernatural into the scientific arena but their further evolution seems delayed by unproductive controversy about whether or not migraine is primarily a vascular or a neurological dysfunction. This conceptual deadlock needs to be transcended by thinking beyond the neural and vascular systems, and by identifying mechanisms that could affect both to produce the characteristic clinical phenomena of migraine. One theoretical model envisages 5-hydroxytryptamine (serotonin; 5-HT) as a link between the neural and vascular systems, with global alteration of serotonergic neurotransmission affecting not only these systems, but the gastrointestinal tract as well, with incidental reverberations on platelet function. Such altered serotonergic transmission might originate from altered 5-HT receptor dynamics, a molecular change in turn produced by genetic mechanisms. Recognition of the importance of 5-HT receptor function in migraine, most notably that agonists of 5-HT1 receptors abort acute migraine and that antagonists of 5-HT2 receptors prevent migraine, may lead to significant therapeutic advances. The possibility that the “trigeminovascular system” might be the end-stage mechanism that these serotonergic changes detonate to produce the painful reverberations of migraine headache is also important. Seeking ways to muffle these reverberations, or to insulate the system itself from the action of external influences (likely through further study of peptidergic transmission and receptors) might result in more drugs that will abort or prevent migraine.