Dysregulated calcium signaling and accumulation of aberrant proteins causing endoplasmic reticulum stress are the early sign of intra-axonal pathological events in many neurodegenerative diseases, and apoptotic signaling is initiated when the stress goes beyond the maximum threshold level of endoplasmic reticulum. The fate of the cell to undergo apoptosis is controlled by Ca2(+) signaling and dynamics at the level of the endoplasmic reticulum. Endoplasmic reticulum resident inositol 1,4,5-trisphosphate receptors (IP3R) play a pivotal role in cell death signaling by mediating Ca2(+) flux from the endoplasmic reticulum into the cytosol and mitochondria. Hence, many prosurvival and prodeath signaling pathways and proteins affect Ca2(+) signaling by directly targeting IP3R channels, which can happen in an IP3R-isoform-dependent manner. Here, in this review, we summarize the regulatory mechanisms of inositol triphosphate receptors in calcium regulation and initiation of apoptosis during unfolded protein response.