Activation of cells by many extracellular agonists leads to the production of inositol 1,4,5-trisphosphate (IP₃). IP₃ is a global messenger that easily diffuses in the cytosol. Its receptor (IP₃R) is a Ca(2+)-release channel located on intracellular membranes, especially the endoplasmic reticulum (ER). The IP₃R has an affinity for IP(3) in the low nanomolar range. A prime regulator of the IP₃R is the Ca(2+) ion itself. Cytosolic Ca(2+) is considered as a co-agonist of the IP₃R, as it strongly increases IP(3)R activity at concentrations up to about 300 nM. In contrast, at higher concentrations, cytosolic Ca(2+) inhibits the IP₃R. Also the luminal Ca(2+) sensitizes the IP₃R. In higher organisms three genes encode for an IP₃R and additional diversity exists as a result of alternative splicing mechanisms and the formation of homo- and heterotetramers. The various IP₃R isoforms have a similar structure and a similar function, but due to differences in their affinity for IP₃, their variable sensitivity to regulatory parameters, their differential interaction with associated proteins, and the variation in their subcellular localization, they participate differently in the formation of intracellular Ca(2+) signals and this affects therefore the physiological consequences of these signals.