Worldwide, cardiovascular disease is a leading cause of morbidity and mortality. Heart failure occurs after a myocardial infarction because natural repair mechanisms are insufficient to replace lost cardiac cells and restore function. Our group is using cell therapy (cell transplantation into the myocardial scar tissue) to regenerate the damaged myocardium and restore cardiac function after a myocardial infarction. In 1996, we published the first demonstration that cells transplanted into myocardial scar tissue survived, differentiated into muscle tissue, and improved heart function. More recently, we have defined optimal cell types for transplantation, and described many of the optimal conditions under which the transplanted cells can achieve the most efficient repair. Currently, we are attempting to determine the mechanisms by which transplanted cells exert their beneficial effects. Clarifying these mechanisms will allow us to develop the “next generation” of gene-enhanced cells for transplantation (cell-based gene therapy). We are also interested in identifying new stem cell niches, and defining the influence of age on the functional effects of cell therapy so that we can improve the therapeutic outcome of this treatment in older patients.