Studies in humans and monkeys have identified structures in the medial temporal lobe essential for memory (the hippocampal re- gion, i.e., the dentate gyrus, the hippocampus, and the subicular complex, and the adjacent perirhinal, entorhinal, and parahippocampal cortices). Additional work has revealed that for both species, damage limited to the hippocampal region produces less severe memory impairment than damage that includes additional structures within the medial temporal lobe. This work has been based on both neurosurgical lesions and on lesions produced by global ischemia or anoxia. An important issue about ischemic damage is whether the damage identifiable in histopathological examination provides an accurate estimate of direct neural damage or whether additional direct damage might be present that is sufficient to disrupt neuronal function in areas important for memory and sufficient to impair behavioral performance, but not sufficient to progress to cell death and to be detectable in conventional histopathology. This commentary explores the issue of ischemic damage and memory impairment. Although few studies have addressed this issue directly, the currently available data from global ischemia in rats, monkeys, and humans are consistent with the hypothesis that the detectable neuronal damage is responsible for the severity of the observed behavioral impairment. Yet it is also true that this hypothesis has not been the target of very much systematic work. We encourage additional experimental work, especially in rats, that could further illuminate how to evaluate the behavioral effects of ischemic lesions. 0 1996 Wiley-Liss, Inc.