Acquired and inherited diseases of the heart represent a major health care issue in this country and throughout the World. Clinical medicine has made important advancements in the past quarter century to enable several effective treatment regimes for cardiac patients. Nevertheless, it is apparent that even with the best care, current treatment strategies and therapeutics are inadequate for treating heart disease, leaving it arguably the most pressing health issue today. In this context it is important to seek new approaches to redress the functional deficits in failing myocardium. This review focuses on several recent gene, cell and chemical-based experimental therapeutics currently being developed in the laboratory for potential translation to patient care. For example, new advances in bio-sensing inducible gene expression systems offer the potential for designer cardio-protective proteins to be expressed only during hypoxia/ischemia in the heart. Stem cells continue to offer the promise of cardiac repair, and some recent advances are discussed here. In addition, discovery and applications of synthetic polymers are presented as a chemical-based strategy for acute and chronic treatment of diseased and failing cardiac tissue. Collectively, these approaches serve as the front lines in basic biomedical research, with an eye toward translation of these findings to clinically meaningful applications in cardiac disease.