Ca(2 +) plays a pivotal role in excitation-contraction coupling as well as activation of Ca(2 +) -dependent signaling pathways in the myocardium. The two main established Ca(2 +) -dependent pathways during cardiomyocyte hypertrophy are the Ca(2 +) /calmodulin-calcineurin-NFAT and the Ca(2 +) /calmodulin dependent kinases II -HDAC-MEF2. Both pathways are involved in the transcriptional control of many hypertrophic genes. Recently, cyclophilin D, an immunophilin located on mitochondrial inner membrane, has been highlighted as a regulator of calcium-mediated mitochondrial permeability transition in necrotic cardiac cell death.