At sites of vascular injury, platelets rapidly adhere to the exposed subendothelial extracellular matrix, become activated and, together with the coagulation system, form a plug that seals the lesion. This process is essential to prevent blood loss, however, under pathological conditions it may lead to vessel occlusion. Agonist-induced elevation of intracellular Ca²⁺ levels is essential for platelet activation. It occurs through two different mechanisms: Ca²⁺ release from internal stores, involving phospholipase C (PLC)-dependent generation of inositol-1,4,5-trisphosphate (IP₃) and activation of IP₃ sensitive channels in the store membrane, and Ca²⁺ influx across the plasma membrane. Store operated Ca²⁺ entry (SOCE), triggered by store depletion, is the main influx pathway for extracellular Ca²⁺ in platelets, but the molecular mechanism underlying this pathway has long remained elusive. In the last years, however, the Ca²⁺ sensor stromal interaction molecule 1 (STIM1) and the channel protein Orai1 emerged as the key players in platelet SOCE. This review summarizes the current knowledge about the role of these proteins in platelet physiology and thrombus formation and discusses their suitability as antithrombotic targets.