There is strong evidence that severe hypoglycemia can worsen the prognosis in acute stroke. In contrast, the influence of acute hyperglycemia on cerebral ischemia remains controversial. The conflicting results of clinical and experimental studies can partly be explained if different stroke subtypes are regarded separately and the time course of the blood-glucose level during the acute insult is taken into account. Hyperglycemia seems to worsen the neuronal injury during the subacute period of cerebral ischemia if there is insufficient collateral blood supply. Furthermore, it increases the risk of hemorrhagic transformation in this time interval. In contrast, acute hyperglycemia may protect neuronal tissue from structural damage by improving the substrate supply if there is only a moderate decrease in cerebral blood flow. This situation is observed in the penumbra and if good collateral blood supply is provided. We therefore hypothesize that both negative and positive effects of acute hyperglycemia depend on the local cerebral blood flow.