Inositol 1,4,5-trisphosphate receptors (IP₃Rs) are a family of tetrameric intracellular calcium (Ca²⁺) release channels that are located on the sarcoplasmic reticulum (SR) membrane of virtually all mammalian cell types, including smooth muscle cells (SMC). Here, we have reviewed literature investigating IP₃R expression, cellular localization, tissue distribution, activity regulation, communication with ion channels and organelles, generation of Ca²⁺ signals, modulation of physiological functions, and alterations in pathologies in SMCs. Three IP₃R isoforms have been identified, with relative expression and cellular localization of each contributing to signaling differences in diverse SMC types. Several endogenous ligands, kinases, proteins, and other modulators control SMC IP₃R channel activity. SMC IP₃Rs communicate with nearby ryanodine-sensitive Ca²⁺ channels and mitochondria to influence SR Ca²⁺ release and reactive oxygen species generation. IP₃R-mediated Ca²⁺ release can stimulate plasma membrane-localized channels, including transient receptor potential (TRP) channels and store-operated Ca²⁺ channels. SMC IP₃Rs also signal to other proteins via SR Ca²⁺ release-independent mechanisms through physical coupling to TRP channels and local communication with large-conductance Ca²⁺-activated potassium channels. IP₃R-mediated Ca²⁺ release generates a wide variety of intracellular Ca²⁺ signals, which vary with respect to frequency, amplitude, spatial, and temporal properties. IP₃R signaling controls multiple SMC functions, including contraction, gene expression, migration, and proliferation. IP₃R expression and cellular signaling are altered in several SMC diseases, notably asthma, atherosclerosis, diabetes, and hypertension. In summary, IP₃R-mediated pathways control diverse SMC physiological functions, with pathological alterations in IP₃R signaling contributing to disease.