A calcium signal is essential for degranulation, generation of eicosanoids and optimal production of cytokines in mast cells in response to antigen and other stimulants. The signal is initiated by phospholipase C‑mediated production of inositol 1,4,5‑trisphosphate resulting in release of stored Ca2+ from the endoplasmic reticulum (ER) and Golgi. Depletion of these stores activates influx of extracellular Ca2+, usually referred to as store‑operated calcium entry (SOCE), through the interaction of the Ca2+‑sensor, stromal interacting molecule‑1 (STIM1), in ER with Orai1(CRACM1) and transient receptor potential canonical (TRPC) channel proteins in the plasma membrane (PM). This interaction is enabled by microtubular‑directed reorganization of ER to form ER/PM contact points or “punctae” in which STIM1 and channel proteins colocalize. The ensuing influx of Ca2+ replenishes Ca2+ stores and sustains elevated levels of cytosolic Ca2+ ions‑the obligatory signal for mast‑cell activation. In addition, the signal can acquire spatial and dynamic characteristics (e.g., calcium puffs, waves, oscillations) that encode signals for specific functional outputs. This is achieved by coordinated regulation of Ca2+ fluxes through ATP‑dependent Ca2+‑pumps and ion exchangers in mitochondria, ER and PM. As discussed in this chapter, studies in mast cells revealed much about the mechanisms described above but little about allergic and autoimmune diseases although studies in other types of cells have exposed genetic defects that lead to aberrant calcium signaling in immune diseases. Pharmacologic agents that inhibit or activate the regulatory components of calcium signaling in mast cells are also discussed along with the prospects for development of novel SOCE inhibitors that may prove beneficial in the treatment inflammatory mast‑cell related diseases.