The only way for a tissue or organ to survive ischemia is by reperfusion or restoration of the blood flow. However, if the ischemic period is too long reperfusion leads to a Ca2+ overload of the myocardial cells and thereby to cell death. The question is; what are the key events during ischemia which cause this transition from reversible to irreversible injury. In this article we discuss whether acidosis may play a crucial role by inducing Ca2+ release from the sarcolemma and reorganization of membrane components especially the membrane lipids, i.e. lateral phase separation, resulting in membrane protein clustering and changes in lipid asymmetry.