Heart failure remains a leading cause of worldwide morbidity and mortality. Despite recent advances in treatment and our increasing knowledge of pathophysiology and the molecular derangements involved in the failing heart, our ability to affect the underlying cardiac disease processes is limited. In recent years, there has been considerable interest in myocardial gene transfer as both an investigational and potential therapeutic modality. Ultimately, the goal of any such strategy is to reprogramme failing cardiac myocytes and correct the aberrant molecular events causing heart failure. So far, viral vectors have been utilised with success more frequently than any other method of gene delivery in animal models. Studies in animal models and in failing human cardiomyocytes in culture targeting specific molecular pathways, including the beta-adrenergic receptor cascade and the myocyte intracellular calcium handling system, have shown encouraging results and offer hope that gene manipulation may provide novel adjunctive therapeutic modalities for human heart failure.