Cortical spreading depression (CSD) is an intense and steady depolarization of neuroglial membranes, and cessation of spontaneous or evoked synaptic activity. CSD can be evoked by simultaneous depolarization of a minimum volume of brain tissue, such as during cerebral ischemia, trauma, or cortical drug application. Once triggered, it slowly spreads to contiguous areas regardless of functional cortical divisions or arterial territories. A pathophysiological overlap between CSD and migraine aura has long been suspected. Both migraine aura and headache result from CSD. Neurological symptoms during migraine aura spread, and the speed of spread on retinotopic maps is consistent with the speed of CSD in experimental animals. Migraine headache results from CSD‐induced activation of nociceptors in meninges and large blood vessels in concert with modulation of central pain mechanisms. Insights into causes and consequences of CSD have come from studies in animals with genetically modified neuronal Ca2+ channel subtypes that influence CSD threshold; therefore, genetic variations may influence CSD susceptibility in humans. Identification of CSD as an important cause of migraine headache provides new insights into mechanisms leading to an attack, and the potential for development of new prophylactic agents.