The possibility that a significant fraction of cardiac myocyte loss in various disease states occurs through apoptosis has elicited considerable attention in recent years. Evidence from human studies as well as in vitro and animal models of disease has shown that cardiac myocyte apoptosis can be induced by a variety of stimuli and in a number of disease states, including hypoxia, ischemia–reperfusion, myocardial infarction, mechanical stretch, aortic constriction, and heart failure. Because adult cardiac myocytes are terminally differentiated cells, the effects of such loss can never be fully compensated. Interest in cardiomyocyte apoptosis has been fueled by the possibility that once the proximal and distal signals were defined that initiate this pathway of cell removal, it would be possible to develop stategies to selectively interfere with such signaling and prevent the loss of cardiac function. This article examines the evidence for possible proximal stimuli of apoptosis in the heart, including ligand-dependent activation of the membrane receptors for Fas ligand and tumor necrosis factor-α, and, in particular, activation of the tumor suppressor gene p53. It relates what is known about the mechanism by which these stimuli in other cells induce apoptosis and discusses possible strategies for inhibiting apoptosis in the heart.