Cells respond to endoplasmic reticulum (ER) stress through the unfolded protein response (UPR), autophagy and cell death. In this study we utilized casp9(+/+) and casp9(-/-) MEFs cells to determine the effect of inhibition of mitochondrial apoptosis pathway on ER stress-induced cell death, UPR and autophagy. We observed prolonged activation of UPR and autophagy in casp9(-/-) cells as compared with casp9(+/+) MEFs, which displayed transient activation of both pathways. Furthermore we showed that while casp9(-/-) are resistant to ER stress, prolonged exposure leads to the activation of a non-canonical, caspase-mediated mode of cell death.