In recent decades, the concept of a vascular origin of migraine has been replaced by theories based on a neuronal pathophysiology. These theories all involve rapid changes in the functioning of the brain, particularly the brain stem, and the trigeminal nerves. While such paroxysmal changes in function could be the result of altered synaptic transmission, or other physiological changes, they could also be due to changes in the function of voltage-regulated sodium and calcium ion channels. Support for this view of migraine as a channelopathy comes from an examination of the likely mechanism of action of migraine prophylactic drugs. It is the present hypothesis that most of the widely used drugs for migraine prevention work by inhibiting the function of one or both of these ion channels. A review of the laboratory research done on most of the commonly used migraine prophylactic drugs, divided into five classes, reveals that they all may work on sodium channels, calcium channels, or both. If this is the common mechanism of action of migraine prophylactics, it should lead toward the development of more effective prophylactic drugs.