Spreading depression is a fascinating phenomenon that can be provoked by chemical, electrical or mechanical stimuli of the cortex. Spreading depression-like transient depolarizations are observed in the peri-infarct tissue after focal ischemia. The reduction in electrical activity and a negative direct current potential shift propagating over the cortex with a rate of 2-5 mm/minute are the physiological hallmarks. It is thought that spreading depression and peri-infarct depolarizations might play a role in the pathogenesis of migraine and stroke. However, these events have never been detected in humans. This paper reviews the physiological characteristics of spreading depression and peri-infarct depolarizations and discusses their potential role in migraine and stroke.