Despite the enormous scientific efforts that have been made to clarify the pathophysiology of ischemic neuronal injury, the mechanism responsible for neuronal cell death after ischemia remains unclear. Neuronal injury can be roughly classified into three categories: acute ischemic injury, delayed neuronal death and neuronal injury in the penumbra. Flow disturbance known as the noreflow phenomenon and postischemic hypoperfusion is the first limiting factor for neuronal resuscitation after an ischemic insult. Extracorporeal circulation has been tried in an attempt to prevent this blood flow disturbance, but it has become apparent that this is no more effective than conventional resuscitation. Delayed neuronal death seems to be triggered by short exposure to ischemia. Although a molecular mechanism including "glutamate excitotoxicity" has been proposed to explain this phenomenon, the details are still uncertain. The interventional point underlying the protective effect of hypothermia against delayed neuronal death may be the key to understanding its pathophysiology. Neuronal death in the penumbra seems to show deterioration through a mechanism of repeated depolarization "spreading depression", although spreading depression itself has no harmful effect on neurons. The pathophysiological mechanism of spreading depression in combination with flow restriction and other relevant factors related to ischemia remains to be investigated.