Apoptosis of cardiac muscle cells plays important roles in the development of various heart diseases including myocardial infarction and anthracycline-induced cardiomyopathy. Understanding the regulatory mechanisms of cardiac myocyte apoptosis and survival is important for establishing therapeutic strategies against heart disease. Our recent experiments demonstrate that the GATA-4 transcription factor not only mediates cardiac hypertrophy, but also regulates apoptosis and survival of adult cardiac muscle cells. Apoptosis induced by anthracyclines is associated with decreased expression of GATA-4, while the restoration of GATA-4 levels via ectopic expression attenuated the apoptosis. Survival factors of cardiac myocytes such as hepatocyte growth factor and endothelin-1 activate GATA-4, and this signal transduction mechanism at least in part serves to protect the heart against oxidative stress.