Regulation of IP₃ receptors (IP₃Rs) by IP₃ and Ca²⁺ allows regenerative Ca²⁺ signals, the smallest being Ca²⁺ puffs, which arise from coordinated openings of a few clustered IP₃Rs. Cells express thousands of mostly mobile IP₃Rs, yet Ca²⁺ puffs occur at a few immobile IP₃R clusters. By imaging cells with endogenous IP₃Rs tagged with EGFP, we show that KRas-induced actin-interacting protein (KRAP) tethers IP₃Rs to actin beneath the plasma membrane. Loss of KRAP abolishes Ca²⁺ puffs and the global increases in cytosolic Ca²⁺ concentration evoked by more intense stimulation. Over-expressing KRAP immobilizes additional IP₃R clusters and results in more Ca²⁺ puffs and larger global Ca²⁺ signals. Endogenous KRAP determines which IP₃Rs will respond: it tethers IP₃R clusters to actin alongside sites where store-operated Ca²⁺ entry occurs, licenses IP₃Rs to evoke Ca²⁺ puffs and global cytosolic Ca²⁺ signals, implicates the actin cytoskeleton in IP₃R regulation and may allow local activation of Ca²⁺ entry.