Inositol 1,4,5‐trisphosphate (IP₃) is a second messenger that induces the release of Ca²⁺ from the endoplasmic reticulum (ER). The IP₃ receptor (IP₃R) was discovered as a developmentally regulated glyco‐phosphoprotein, P400, that was missing in strains of mutant mice. IP₃R can allosterically and dynamically change its form in a reversible manner. The crystal structures of the IP₃‐binding core and N‐terminal suppressor sequence of IP₃R have been identified. An IP₃ indicator (known as IP₃R‐based IP₃ sensor) was developed from the IP₃‐binding core. The IP₃‐binding core’s affinity to IP₃ is very similar among the three isoforms of IP₃R; instead, the N‐terminal IP₃ binding suppressor region is responsible for isoform‐specific IP₃‐binding affinity tuning. Various pathways for the trafficking of IP₃R have been identified; for example, the ER forms a meshwork upon which IP₃R moves by lateral diffusion, and vesicular ER subcompartments containing IP₃R move rapidly along microtubles using a kinesin motor. Furthermore, IP₃R mRNA within mRNA granules also moves along microtubules. IP₃Rs are involved in exocrine secretion. ERp44 works as a redox sensor in the ER and regulates IP₃R1 activity. IP₃ has been found to release Ca²⁺, but it also releases IRBIT (IP₃R‐binding protein released with IP₃). IRBIT is a pseudo‐ligand for IP₃ that regulates the frequency and amplitude of Ca²⁺ oscillations through IP₃R. IRBIT binds to pancreas‐type Na, bicarbonate co‐transporter 1, which is important for acid‐base balance. The presence of many kinds of binding partners, like homer, protein 4.1N, huntingtin‐associated protein‐1A, protein phosphatases (PPI and PP2A), RACK1, ankyrin, chromogranin, carbonic anhydrase‐related protein, IRBIT, Na,K‐ATPase, and ERp44, suggest that IP₃Rs form a macro signal complex and function as a center for signaling cascades. The structure of IP₃R1, as revealed by cryoelectron microscopy, fits closely with these molecules.