A combination of basic science and human physiology, particularly functional neuroimaging, has radically altered our understanding of migraine with a focus on brain mechanisms for this common and disabling disorder. Genetic studies have begun to provide plausible targets for the basic molecular defect in terms of ion channels, albeit thus far in the rare condition of familial hemiplegic migraine (FHM). Migraine pathophysiology involves the trigeminovascular system and central nervous system modulation of the pain-producing structures of the cranium. The degree to which head pain results from the activation of the nociceptors of pain-producing intracranial structures, or to the facilitation or lack of inhibition of afferent signals, is not clear at this time. An understanding of the pain mechanism is likely to provide insights into the mechanisms underlying the more generalized sensory dysfunction that is so typical of migraine.