Atrial fibrillation (AF) is associated with substantial structural changes at cell and tissue level. Cellular hypertrophy, disintegration of sarcomeres, mitochondrial swelling and apoptosis have been described as typical histo-morphologic alterations in AF. Main initiators for cellular alterations in fibrillating atrial myocytes are cytosolic calcium overload and oxidative stress. Calpains are intracellular Ca²⁺- activated proteases and important mediators of calcium overload. Activation of calpains and down-regulation of the calpain inhibitor, calpastatin, contribute to myocardial damage in fibrillating atria. Thus, deregulations of the expression, activity, or subcellular localization of calpain within atrial myocytes have been established as important mediators of atrial myopathy during AF.