We investigated the mechanisms of 1) ischemia-induced neuronal cell death and 2) acquisition of tolerance against ischemic stress in glial cells. Hypoxia, an ischemic stress, induced neuronal apoptosis via cytochrome c release from mitochondria and following caspase activation. On the other hand, this stress up-regulated some stress proteins such as a 70 kDa heat-shock protein (HSP70) and a 78 kDa glucose-regulated protein (GRP78). In addition, we found that HSP70 induction was sensitive to SB203580, suggesting that p38 MAP kinase was positively involved in this expression. We further attempted to identify a stress protein that was enhanced or induced by hypoxia or brain ischemia in glial cells. We isolated protein-disulfide isomerase (PDI) as a candidate protein and this protein certainly induced in glial cells of ischemic brain. Overexpression of PDI in vitro and in vivo resulted in attenuation of the loss of cell viability in neuroblastoma SK-N-MC cells and a reduction in the number of DNA-fragmented cells in the CA1 subfield of the hippocampus in brain ischemic rats, respectively. Thus, up-regulated PDI may play a critical role in resistance to ichemic damage.