The Characteristic form and development of sensory disturbances during migraine auras suggests that the underlying mechanism is a disturbance of the cerebral cortex, probably the cortical spreading depression (CSD) of Leão. The demonstration of unique changes of brain blood flow during attacks of migraine with aura, which have been replicated in animal experiments during CSD, constitutes another important line of support for the ‘spreading depression’ theory, which may be a key to an understanding of the migraine attack. Cortical spreading depression is a short-lasting depolarization wave that moves across the cortex at a rate of 3–5 mm/min. A brief phase of excitation heralds the reaction which is immediately followed by prolonged nerve cell depression synchronously with a dramatic failure of brain ion homeostasis, efflux of excitatory amino acids from nerve cells and enhanced energy metabolism. Recent experimental work has shown that CSD in the neocortex of a variety of species including man is dependent on activation of a single receptor, the N-methyl-D-aspartate receptor, one of the three subtypes of glutamate receptors. The combined experimental and clinical studies point to fruitful areas in which to look for migraine treatments of the future and provide a framework within which important aspects of the migraine attack can be modelled.