Activation of non- excitable cells involves the agonist-induced elevation of cytosolic Ca2+, an essential process for platelet activation. It occurs through Ca2+ release from intracellular stores and Ca2+ entry through the plasma membrane. Ca2+ store release involves phospholipase C (PLC)-mediated production of inositol-1,4,5-trisphosphate (IP3), which in turn stimulates IP3 receptor channels to release Ca2+ from intracellular stores. This is followed by Ca2+ entry into the cell through plasma membrane calcium channels, a process referred to as store-operated calcium entry (SOCE). Stromal interaction molecule 1 (STIM1), a Ca2+ sensor molecule in intracellular stores, and the four transmembrane channel protein Orai1 are the key players in platelet SOCE. Other major Ca2+ entry mechanisms are mediated by the direct receptor-operated calcium (ROC) channel, P2X1 and transient receptor potential channels (TRPCs).