Advanced heart failure represents a major unmet clinical need, arising from the loss of viable and/or fully functional cardiac muscle cells. Despite optimum drug therapy, heart failure represents a leading cause of mortality and morbidity in America. A major challenge in drug development is the identification of cellular assays that accurately recapitulate normal and diseased human myocardial physiology in vitro. Current approaches for drug discovery are based on animal model systems and consist of either in vivo toxicology or in vitro cellular assays on rodent (rat and mouse) neonatal cardiac myocytes. Although these approaches have been useful in the past, important differences exist between rodent and human cardiomyocytes as well as between normal and diseased human cardiomyocytes. Generating functional myocardial tissue from a renewable patient-specific source would be a major advance in the field: It would allow for the development of disease specific cellular assays for drug development and discovery and would lay the foundation for cardiac regenerative medicine. Embryonic stem (ES) cells and, more notably, induced pluripotent stem (iPS) cells represent a potentially renewable patient-specific source of ventricular progenitor cells and mature ventricular myocytes. Recent studies have allowed for the identification, purification, and renewal of cardiovascular progenitors from both murine and human ES and iPS cells. Our goal is to couple tissue engineering technologies with stem cell and developmental biology for the generation of human model systems of human disease.