Co-regulation of IP3 receptors (IP3Rs) by IP3 and cytosolic Ca2+ allows them to mediate regenerative signals, amongst which are Ca2+ puffs. These reflect the near-simultaneous opening of a few IP3Rs within a small cluster. A long-standing conundrum is the observation that while most IP3Rs appear to be mobile, Ca2+ puffs repeatedly initiate from a limited number of fixed sites. Using gene-editing to attach GFP to endogenous IP3Rs in HeLa cells has allowed the distribution of IP3Rs and the Ca2+ signals they evoke to be imaged simultaneously. This approach shows that most endogenous IP3Rs are loosely assembled into small clusters, most of which are mobile. However, the Ca2+ puffs evoked by histamine or photolysis of caged IP3 invariably initiated at immobile IP3R clusters adjacent to the plasma membrane (PM). Hence, only a small fraction of cellular IP3Rs are 'licensed' to respond. The licensed IP3R clusters sit alongside the sites where store-operated Ca2+ entry (SOCE) occurs, suggesting that the IP3Rs may allow local regulation of SOCE.