Ischemic stroke is a major disabling disease. There are 500,000 new cases in U.S. every year, and the middle cerebral artery (MCA) is the artery most often occluded. In this paper recent results of experimental MCA occlusion are reviewed, with special emphasis on those factors contributing to irreversible damage. Occlusion of MCA in the rat causes a pronounced decline of flow in the neostriatum to less than 10% of normal. The area of low flow is surrounded by a zone 0.2-0.5 mm wide, across which blood flow increases steeply. Beyond this zone, changes in flow are more gradual, and perfusion is reduced to about 1/3 of normal in the adjacent ipsilateral cortex. The MCA occlusion leads to a sharply demarcated infarct and to scattered neuronal injury in the adjacent cortical tissue. It is suggested that the ischemic core is identical with the tissue infarct, i.e. that it is the initial pattern of blood flow which determines the volume and topography of infarction. Waves of spreading depression are detected in the cortical low perfusion area during the first hours of MCA occlusion, and glucose consumption is increased, presumably due to an increased demand for ionic transport. In hyperglycemic animals, the number of spreading depressions is reduced as is the glucose consumption. The repeated waves of spreading depression in combination with partial energy depletion may induce selective neuronal injury in the peri-infarct zone, a suggestion which finds support in the fact that hyperglycemia ameliorates neuronal injury around the infarction.