This article reviews the experimental evidence suggesting that cytosolic Ca²⁺ overload plays a major role in the development of myocardial injury during ischemia–reperfusion and that Ca²⁺ release from the sarcoplasmic reticulum (SR) is of crucial importance in the early phase of ischemia. It is suggested that interventions able to deplete the SR Ca²⁺ pool and/or to reduce the rate of SR Ca²⁺ release should be cardioprotective. This thesis is supported by the review of experimental studies in which modulators of the SR Ca²⁺-ATPase or SR Ca²⁺ release channel (ryanodine receptor) have been used. In addition, the role of the SR in ischemic preconditioning and in some instances of toxic myocardial injury (particularly, anthraquinone-induced injury) is discussed.