Calcium ions play an important role as secondary messenger in cell biology therefore, regulation of its cellular concentration is key to maintain homeostasis and trigger signaling events. A multitude of pathways have been developed during evolution to tightly control the in and out of cellular calcium ions. Store-operated calcium entry (SOCE) is a major signaling pathway involved in proper development of muscle cells and immune system activation. During SOCE, an agonist stimulation generates inositol trisphosphate (IP3) from phosphatidylinositol 4,5-biphosphate (PIP2) hydrolysis. Following, IP3 induces depletion of endoplasmic reticulum (ER) calcium store through IP3 receptor (IP3R). Stromal interaction protein 1 (STIM1), an ER transmembrane protein, senses calcium depletion through its luminal domains which induce a conformational change exposing key cytosolic domains. STIM1 new intramolecular arrangement favors its oligomerization and in turn its translocation to cortical ER (cER), which is closely apposed to plasma membrane (PM). Within those ER-PM junctions, STIM1 binds and gate ORAI1 calcium channel on the PM and induce calcium entry. Refilling of the ER store and cytosolic calcium elevations are responsible for SOCE termination due to loss of STIM-ORAI complexes though calcium dependent inactivation processes.