Inositol 1,4,5-trisphosphate receptors (IPR) are the most widely expressed intracellular Ca release channels. Their activation by IP and Ca allows Ca to pass rapidly from the ER lumen to the cytosol. The resulting increase in cytosolic [Ca] may directly regulate cytosolic effectors or fuel Ca uptake by other organelles, while the decrease in ER luminal [Ca] stimulates store-operated Ca entry (SOCE). We are close to understanding the structural basis of both IPR activation, and the interactions between the ER Ca-sensor, STIM, and the plasma membrane Ca channel, Orai, that lead to SOCE. IPRs are the usual means through which extracellular stimuli, through ER Ca release, stimulate SOCE. Here, we review evidence that the IPRs most likely to respond to IP are optimally placed to allow regulation of SOCE. We also consider evidence that IPRs may regulate SOCE downstream of their ability to deplete ER Ca stores. Finally, we review evidence that IPRs in the plasma membrane can also directly mediate Ca entry in some cells.