Cardiac dysfunction due to ischemia-reperfusion (I/R) is associated with marked changes in membrane function and subsequent Ca2+-handling abnormalities in cardiomyocytes. The membrane abnormalities in hearts subjected to I/R arise primarily from oxidative stress as a consequence of increased formation of reactive oxygen species and other oxidants, as well as reduced antioxidant defenses. Little is known, however, about the nature and mechanisms of the sarcolemmal membrane changes with respect to phospholipase C (PLC)-related signaling events. In addition, the mechanisms involved in protection of the postischemic myocardium and in ischemic preconditioning with respect to PLC function need to be established. Accordingly, this article reviews the historical and current information on PLC-mediated signal transduction mechanisms in I/R, as well as outlining future directions that should be addressed. Such information will extend our knowledge of ischemic heart disease and help improve its therapy.