Abstract: The loss of homeostasis regulation of calcium ion (Ca²⁺) in myocardium is the pathological basis of many heart diseases and it is closely related to myocardial ischemia-reperfusion injury. Altered Ca²⁺ regulation in and out of cells induced by ischemia-reperfusion lead to calcium overload in cytoplasm and mitochondrial matrix. Cell damage, dysfunction or electrophysiological disorder occur as a result of energy-dependent hypercontraction of myocardial fibers, calpain-mediate hydrolysis of cell proteins, opening of mitochondrial permeability transition pores, apoptosis and uncoupling cell activation related to closed gap junctions. Modulation of different steps of the Ca²⁺ cycle, correcting or maintaining calcium homeostasis, has been proven to be helpful for prevention or mitigation of myocardial ischemia-reperfusion injury.