Calpains, a family of Ca2+-dependent cysteine proteases, can modulate their substrates structure and function through limited proteolytic activity. Calpain mediated proteolysis of intracellular proteins is a key step in various cellular processes such as cytoskeleton modulation, cell migration, cell cycle progression and apoptosis. Calpain activity is controlled in vivo by calpastatin, a multiheaded endogenous polypeptide encoded by the calpastatin gene that specifically inhibits calpain. Calpains have previously been considered as the cytoplasmic enzymes; however, recent research have demonstrated that m-calpain and calpastatin are present in endoplasmic reticulum and play important roles in a variety of pathophysiological conditions including necrotic and apoptotic cell death phenomena. This review summarizes function and regulation of the endoplasmic reticulum calpain system, focusing on the relevance of its roles in several cellular and biochemical events under normal and some pathophysiological conditions.