Cardiomyocyte death resulting from apoptosis has been implicated in the evolution of heart failure. In this review, we focus on the concept that the cardiotoxicity of excessive sympathetic nervous system activity observed in heart failure is in part due to myocytes death by apoptosis. In vitro, high doses of norepinephrine induce adult cardiomyocyte apoptosis via 3-adrenergic receptor-coupled signaling pathways (PKA and Ca2+ entry-dependent mechanisms). beta1-and beta2-AR co-exist in the cardiac cell. beta1-AR stimulation is pro-apoptotic, whereas beta2-AR stimulation is anti-apoptotic, mediating its protective effect via coupling to Gi. These in vitro observations have been confirmed in transgenic mice: cardiac beta1-AR overexpression increases apoptosis and leads to heart failure, whereas cardiac beta2-AR overexpression has no deleterious effects. beta-AR stimulation activates p38 kinases and JNK (via the small GTP protein Rac1); and exert anti- and pro-apoptotic effects, respectively. Other studies suggest that beta1-AR-stimulated apoptosis is dependent on Ca2+ -activated calmodulin kinase II and that the anti-apoptotic effect of beta2-AR is mediated via Akt-coupled pathways. beta-AR-stimulated apoptosis involves the mitochondrial pathway. Inhibition of mitochondrial permeability transition pore opening or caspase activation decreases beta-AR-stimulated apoptosis. Reactive oxygen species production is also involved in this process since superoxide dismutase/catalase-mimetics or catalase overexpression prevent beta-AR-stimulated apoptosis. In vivo, it has been shown that beta-AR blockers such as metoprolol and carvedilol have beneficial effects in animal models of chronic heart failure, associated with reduced apoptosis and improved cardiac systolic function. Understanding the mechanisms involved in the control of myocyte loss by the beta-adrenergic system will have direct clinical implications by improving the treatment of heart failure.