This perspective discusses cortical spreading depression (CSD) phenomena and their translational significance for human migraine aura and the peri-infarct events following cerebral ischemia and injury. They begin with interstitial K(+) release and accumulation following neuronal stimulation, and a buffering astrocytic K(+) influx and remote liberation propagating waves of neuronal hyperexcitability and depression. Diffusion-weighted echoplanar MRI demonstrates CSD features in gyrencephalic brains recapitulating human migraine aura, spatial and temporal features of single primary events and multiple secondary events, their stimulus dependence, pharmacological properties, and their relationship to blood oxygenation level-dependent signals and late cerebrovascular changes. The article finally explores prospects for physiological studies of CSD gaining fuller insights both into mechanisms underlying the pathology of the corresponding human condition and possible approaches to management.