Natriuretic peptides (NPs) have emerged as important candidates for development of therapeutic agents in cardiovascular disease. For example, infusion of a recombinant form of mature B-type natriuretic peptide (BNP) has been used clinically in heart failure for its vasodilatory properties, but its use has been limited by hypotension and concerns regarding worsening of renal function. Since BNP has important autocrine, paracrine, and endocrine actions that are mediated through the guanylyl cyclase (GC)-A receptor and activation of cGMP in target cells, we established a novel therapeutic strategy to augment the biological actions of NP system by locally increasing BNP levels in the heart using adenovirus-mediated gene delivery. These studies indicated that BNP gene delivery has unique pleiotropic, context-dependent, favorable actions on cardiac function. Local BNP gene delivery into the rat adult heart improved left ventricular contractility during the remodeling process both after infarction and in response to pressure overload. Moreover, in healthy heart, local increase in left ventricular BNP peptide levels by gene delivery was antifibrotic and angiogenic without affecting systolic function. Interestingly, the favorable effect of BNP on cardiac function after infarction but not in angiotensin II–induced hypertension was associated with normalization of SERCA2 expression and phosphorylation of phospholamban. Thus, it would be attractive to develop novel pharmacological therapies for the enhancement of BNP function selectively in the heart and to investigate whether phosphodiesterase inhibitors or novel direct guanylate cyclase activators modify the favorable antifibrotic and angiogenic effects of BNP gene delivery on cardiac function.