This project investigates stem cell–based strategies for cardiac regeneration with a focus on engineered heart tissue (EHT). Pluripotent stem cells, capable of generating large numbers of cardiomyocytes and endothelial cells, were explored for their therapeutic potential in restoring myocardial function. Using a fibrin-based EHT patch in rabbits, transplantation led to improved cardiac function, as demonstrated by increased fractional area change, reduced infarct size, robust neovascularization, and proliferation of transplanted cardiomyocytes. However, retention of cells was significantly lower in infarcted hearts, largely due to immune-mediated loss, highlighting the challenge of long-term cell survival. To address the xenogeneic immune barrier, syngeneic rabbit iPSCs were differentiated toward the cardiac lineage, though achieving efficient cardiomyocyte generation remained a limitation. Overall, this work underscores the promise of stem cell–derived EHTs for repairing injured myocardium while outlining the key hurdles that must be overcome to translate these approaches toward clinical application.