Human heart failure is preceded by a process termed cardiac remodeling in which heart chambers progressively enlarge and contractile function deteriorates. Programmed cell death (apoptosis) of cardiac muscle cells has been identified as an essential process in the progression to heart failure. The execution of the apoptotic program entails complex interactions between and execution of multiple molecular subprograms. Unlike necrosis, apoptosis is an orderly regulated process and, by inference, a logical therapeutic target if intervention occurs at an early stage. To identify potential therapeutic targets, it is imperative to have a full understanding of the apoptotic pathways that are functional in the cardiac muscle. Accordingly, the present review summarizes the apoptotic pathways operative in cardiac muscle and discusses therapeutic options related to apoptosis for the future treatment of human heart failure.