Congestive heart failure (CHF) remains a leading cause of morbidity and mortality in the United States and in many other countries. Current heart failure therapies, including multidrug treatment regimens, biventricular pacing, and mechanical support such as left ventricular assist devices, are often hindered by limited benefits or significant associated procedural complications or side effects. Therefore, new forms of treatment, which could ideally target the underlying biological processes affecting the ailing cardiomyocyte, would be of significant potential benefit to the population of individuals with CHF. Gene transfer strategies, including modification of cellular contractile signaling and regulatory pathways, represent a promising new form of such biologic therapy for heart disease.