The inositol 1,4,5 trisphosphate (IP₃) receptor (IP₃R) is a Ca²⁺ release channel that responds to the second messenger IP₃. Exquisite modulation of intracellular Ca²⁺ release via IP₃Rs is achieved by the ability of IP₃R to integrate signals from numerous small molecules and proteins including nucleotides, kinases, and phosphatases, as well as nonenzyme proteins. Because the ion conduction pore composes only ∼5% of the IP₃R, the great bulk of this large protein contains recognition sites for these substances. Through these regulatory mechanisms, IP₃R modulates diverse cellular functions, which include, but are not limited to, contraction/excitation, secretion, gene expression, and cellular growth. We review the unique properties of the IP₃R that facilitate cell-type and stimulus-dependent control of function, with special emphasis on protein-binding partners.