Calpain, a Ca2+activated intracellular protease and its endogeneous protein inhibitor, calpastatin are abundant in platelets. The structure and enzymological properties of calpain, including its isozymes, and of calpastatin in platelets have been fully characterized. Also, platelet calpain has been shown to cleave various endogeneous polypeptides. However, the mode of activation and the physiological function of platelet calpains have not been clarified. Our recent investigations on platelet calpains with cell permeable calpain antagonists and specific antibodies reveal that calpains are not involved in the early phases of platelet activation such as shape change and aggregation, but in the later phases of platelet activation such as cytoskeletal reorganization and Ca2+uptake.