Inositol 1,4,5-trisphosphate receptors (IP3Rs) are intracellular Ca2+ channels. They allow cell-surface receptors that stimulate IP3 formation to evoke rapid Ca2+ release from the endoplasmic reticulum (ER). IP3Rs initiate local and global cytosolic Ca2+ signals, they deliver Ca2+ selectively to other organelles including mitochondria and lysosomes, and, by depleting the ER of Ca2+, they control store-operated Ca2+ entry (SOCE). We consider two areas where recent work highlights the importance of liaisons between IP3Rs and other intracellular membranes. Interactions between IP3Rs and lysosomes illustrate striking parallels with the relationships between IP3Rs and mitochondria. In each case, the ER concentrates Ca2+ from the cytosol and then delivers it through IP3Rs to a low-affinity Ca2+-uptake system in a juxtaposed organelle. Evidence that only immobile IP3Rs parked alongside the sites where SOCE occurs suggests a mechanism whereby local depletion of the ER may activate SOCE without compromising other Ca2+-dependent ER functions.