The clinical efficiency of thrombolysis is explained by the rescue of ischemic penumbra areas resulting from early arterial recanalization. The perfusion-diffusion weighted imaging mismatch is a commonly used MRI surrogate of the ischemic penumbra. However, the randomized trials testing the mismatch hypothesis have been negative. We will review the 'mismatch concept' and the recent studies that aim to localize the clinically eloquent areas of penumbra in middle cerebral artery (MCA) infarcts. New methods of image analysis have shown that poor outcomes after MCA stroke are related to infarction of an extremely well localized area of the periventricular white matter and adjacent internal capsule, where projections and association tracts are crossing and converging. This area almost colocalizes with the area salvaged by early arterial recanalization and is located extremely close to the initial ischemic core. The location of the area that correlates with disability in MCA stroke patients and that is salvaged by early arterial recanalization is in the same specific region of the deep white matter, close to the initial ischemic core. These findings may have important implications for designing new recanalization trials and support the importance of basic research on white-matter neuroprotection.