Heart failure remains the leading cause of mortality in the USA, despite major advances in therapy over the past several decades, including angiotensin-converting enzyme or angiotensin II inhibitors, vasodilators, calcium-channel blockers and beta-adrenergic receptor blockers. New therapeutic approaches are clearly required and the conceptual origin of these new techniques will be derived from agents that protect the heart against stress and prolong longevity. The combination of stress protection and longevity has been observed in a variety of organisms, from yeast to worms to mammals, and could be the basis for a novel approach to heart failure therapy. A mouse model has been developed with genetic disruption of adenylyl cyclase type 5, which lives one-third longer than the wild-type and is protected from aging-induced, pressure overload-induced and catecholamine-induced stresses. Accordingly, inhibition of this molecule should be considered as a new therapeutic modality for heart failure.