IP3 receptors act as Ca2+ channels to control vital phenomena and disorders, but the fundamental mechanism of how IP3 opens the channel remains elusive. The recent advances in cryo-electron microscopy has enabled the construction of a near atomic model of the tetrameric IP3 receptor. The most recent X-ray crystallography demonstrated that binding of IP3 resulted in global allosteric conformational changes of the large cytosolic domain. Further, functional analyses revealed that a unique leaflet structure transmits the conformational changes to the channel upon activation of IP3 receptors by IP3. In this review, we outline recent evidence for the gating mechanism of the IP3 receptor, and discuss remaining unsolved issues.