Migraine with aura is characterized by recurrent attacks of visual and, occasionally, sensory, language and/or motor disturbances, typically followed by headache. Migraine with aura can be associated with allodynia and vascular and psychiatric comorbidities. The electrophysiological cause of the aura is cortical spreading depolarization, a wave of depolarization that propagates slowly across the cortical surface, producing reversible metabolic and electrochemical perturbations. In this Review, we focus on the relationship of spreading depolarization with migraine aura and migraine headache. Abundant evidence causally links spreading depolarization to the headache phase of migraine with aura, as it can activate trigeminal nociceptors, produce dural and cortical inflammation, and induce trigeminal pain behaviour in rodents. In experimental models, migraine prophylaxis reduces susceptibility to spreading depolarization, and abortive treatments abrogate trigeminal pain behaviour that is induced by spreading depolarization. Although questions remain about the role of spreading depolarization in migraine with aura and models of spreading depolarization need to be refined, the cumulative evidence suggests that spreading depolarization is a putative target for therapeutic intervention in migraine. Elucidating the mechanisms by which spreading depolarization can induce trigeminal pain could facilitate drug discovery, and models of spreading depolarization could be effective screening platforms for migraine therapies.