Mechanisms accounting for the cellular entry of calcium that mediates cellular proliferation and apoptosis have been obscure. Previously we reported selective augmentation of type 3 inositol (1,4,5) trisphosphate receptors (IP₃R3) in lymphocytes undergoing programmed cell death, which was prevented by antisense constructs to IP₃R3. We now report increases in mRNA and protein levels for IP₃R3 associated with cell death in several apoptotic paradigms in diverse tissues. Elevations of IP₃R3 occur during developmental apoptosis in early postnatal cerebellar granule cells, dorsal root ganglia, embryonic hair follicles, and intestinal villi. Neurotoxic damage elicited by the glutamate agonist kainate is also associated with IP₃R3 augmentation. In chick dorsal root ganglia neurons undergoing apoptosis due to deprivation of nerve growth factor, levels of IP₃R3 are selectively increased and cell death is selectively prevented by antisense oligonucleotides to IP₃R3. Thus, IP₃R3 appears to participate actively in cell death in a diversity of tissues.—Blackshaw, S., Sawa, A., Sharp, A. H., Ross, C. A., Snyder, S. H., Khan, A. A. Type 3 inositol 1,4,5‐trisphosphate receptor modulates cell death. FASEB J. 14, 1375–1379 (2000)