Changes in the cytoplasm free Ca²⁺ concentration [Ca²⁺]_in regulate a large number of relevant physiological processes and have a major impact on cell development and function. The identification of STIM, the endoplasmic reticulum (ER) Ca²⁺ sensor, and Orai, a key subunit of the Ca²⁺ release-activated Ca²⁺ (CRAC) channel pore, have provided the tools to illuminate the mechanisms of CRAC channel regulation, that play an important role in modulation of the free Ca²⁺ concentration in non-excitable cells. Store-operated Ca²+ entry (SOCE) is a common and ubiquitous mechanism for regulating Ca²⁺ influx into cells and is widely expressed in most tissues.