Heart failure is a leading cause of death in developed countries. Recent advances in interventional cardiology and cardiac surgery have made it possible to save numerous patient lives after myocardial infarction. However, those patients eventually develop end-stage heart failure since the loss of cardiac muscle is never replaced with new muscle. Our study focus is on regenerating cardiac muscle by transdifferentiating cardiac fibroblasts into cardiomyocytes. We reported that Gata4, Mef2c, and Tbx5 overexpression transdifferentiated cardiac fibroblasts into cardiomyocyte-like cells in vitro, and improved cardiac function in vivo. Our goal is to translate this in-situ cardiomyocyte regeneration into clinical therapy.