Carboxy terminus of Hsc70 Interacting Protein (CHIP) is thought to be a cytoprotective protein with roles in protein quality control in neurodegenerative diseases and myocardial ischemia. This study examined CHIP expression in normal mouse brain and in primary cultures of cortical neurons following heat stress (HS) and oxygen-glucose deprivation (OGD). CHIP was highly expressed throughout the brain, predominantly in neurons where the staining pattern was primarily cytoplasmic. More intense nuclear staining was observed in primary cultured cells than in brain sections. Nuclear accumulation of CHIP occurred very rapidly after 5-10 minutes of HS and decreased at or below baseline by 30-60 minutes. Increased durations of HS gave rise to sharp increases in delayed cell death and were inversely correlated with the loss of nuclear CHIP. While no changes in cytoplasmic CHIP were observed immediately following OGD, nuclear levels of CHIP increased slightly in response to OGD by 30 minutes and remained increased through 240 minutes. Increased CHIP levels did not decrease immediately following extended durations of OGD, but rather decreased during recovery following OGD. Nuclear CHIP decreased earlier in recovery following 120 minutes of OGD (4 hours) than 30 minutes of OGD (12 hours). Significant cell death first appeared between 12 and 24 hours after OGD again suggesting that delayed cell death follows closely behind the disappearance of nuclear CHIP. Cell viability in heterozygous and homozygous hippocampal slice cultures from transgenic mice lacking CHIP was impaired following OGD. Transgenic cultures displayed increased delayed cell death following 30 minutes of OGD compared to wildtype. Following 120 minutes of OGD, cell death in all cultures was greater than baseline but cell death in the transgenic samples was no longer significantly greater when compared to wildtype. A yeast two-hybrid screen to identify proteins that interact with full-length recombinant CHIP yielded 19 sequences from known binding partners heat shock protein 70 and heat shock protein 90. Together the results support the idea that the ability of CHIP to translocate to and accumulate in the nucleus may be a limiting variable that determines how effectively cells respond to external stressors to facilitate cell survival.