This is a speculative review of the role of the lysosome in ischemic cell death in the mammalian brain. In particular, it focuses on the role of the permeabilization of the lysosomal membrane to proteins (LMP) as a major mechanism of cell death in mild, but lethal, ischemic insults. The first section of the review outlines the evidence that this is the case, using the relatively few extant studies of mammalian brain. In the second section of the review, the mechanism by which an ischemic insult might lead to LMP is discussed. A metabolic sequence including NMDA receptor activation, activation of phospholipase A2 and production of free radicals, and also the activation of calpain are shown to be critical. The remainder of the section speculates on the actual agent(s) which may be causing the lysosomal membrane change, based on extensive literature references. There is currently no knowledge of the actual mechanism. The third section considers potential targets of the released lysosomal proteases and other proteins that might mediate the lethal effects of LMP, focusing largely on the mitochondria as the target. Again, this is speculative as the targets are not known. Finally, the fourth section addresses the level of importance that LMP has in the process of ischemic cell death and concludes that it may well play the major role during mild but lethal ischemic insults. This novel, so-called "lysosomocentric," hypothesis is briefly critiqued. The therapeutic potential of this conclusion is then discussed.