Migraine and epilepsy are comorbid episodic disorders that have common pathophysiologic mechanisms. Migraine attacks, like epileptic seizures, may be triggered by excessive neocortical cellular excitability; in migraine, however, the hyperexcitability is believed to transition to cortical spreading depression rather than to the hypersynchronous activity that characterizes seizures. Some forms of epilepsy and migraine are known to be channelopathies. Mutations in the same genes can cause either migraine or epilepsy or, in some cases, both. Given the likely commonalities in the underlying cellular and molecular mechanisms, it is not surprising that some antiepileptic drugs, including valproate, topiramate, and gabapentin, are effective antimigraine agents. Ionotropic glutamate receptors play roles in both migraine and epilepsy, with NMDA receptors that are critical to cortical spreading depression of particular importance in migraine. Greater understanding of the shared mechanisms of epilepsy and migraine can provide a basis for the development of improved treatment approaches that may be applicable to both conditions.