Despite the progress that has been made over the past two decades in cardiovascular research, heart failure remains a major cause of morbidity and mortality worldwide. Insight into the cellular and molecular mechanisms that underlie the heart failure in individuals with ischemic heart disease have identified defects in cellular processes that govern autophagy, apoptosis and necrosis as a prevailing underlying cause. Indeed, programmed cell death of cardiac cells by apoptosis or necrosis is believed to involve the intrinsic mitochondrial pathway and/or extrinsic death receptor pathway by certain Bcl-2 family members as well as components of the TNFα signaling pathway. In this review, we discuss recent advances in the molecular signaling factors that govern cardiac cell fate under normal and disease conditions.