Cell loss is a common feature in the failing heart, and this contributes to the relentless progression seen in patients with heart failure. Apoptosis is one of the most common causes of cell loss in animals and humans with heart failure. There is increasing evidence that apoptosis, even while occurring in a low-grade manner, can mediate heart failure. Moreover, inhibiting apoptosis successfully prevents or attenuates heart failure in several animal models. More importantly, apoptosis is one of the few mechanisms that can be easily modulated using pharmacologic or gene therapy approaches. Animal data, obtained in the past few years, have proven the feasibility and success of this approach toward altering the natural history of heart failure. Human studies are pending, but a number of issues such as the type of inhibitor and its optimum timing/dose will need to be resolved before this becomes a reality. Nevertheless, these data will accrue over time, and antiapoptotic therapy is likely to emerge as an important form of heart failure therapy.