Migraine is the most common neurologic condition. One-third of migraineurs experience transient neurologic symptoms, the so-called aura. There is strong evidence that spreading depression (SD) is the electrophysiologic substrate of migraine aura. SD is an intense pan-depolarization wave that slowly propagates in gray matter by way of contiguity and transiently disrupts neuronal function. When induced subcortically, striatal SD causes hemiparesis, hippocampal SD can trigger seizures and impact cognition, and bilateral thalamic SD can diminish consciousness. Recent data show that transgenic mice expressing familial hemiplegic migraine (FHM) type 1 mutations in voltage-gated Ca2+ channels (Cav2.1) develop mutation-specific aura-like signs after a cortical SD similar to patients with the respective mutation. These signs are associated with facilitated subcortical SD propagation. As in FHM, mice with the R192Q mutation develop pure hemiplegia associated with cortical SDs propagating into caudoputamen. S218L mice display additional signs such as seizures and coma when SD propagates into hippocampus and thalamus. In hyperexcitable FHM brains, SD may propagate between cortex and subcortical structures via permissive gray matter bridges, or originate de novo in subcortical structures, to explain unusual and severe aura signs and symptoms. Reciprocal spread and reverberating waves can explain protracted attacks.