Heart failure due to cardiomyocyte loss and pump dysfunction after ischemic heart disease is the leading cause of death in the United States. We strive to facilitate cardiac regeneration after heart damage to improve survival rates. Limited endogenous adult cardiomyocyte regenerative potential after acute damage results from inadequate adult cardiomyocyte proliferative capacity. Strikingly, the mammalian heart endogenously replaces merely 1% of cardiomyocytes per year. In our previous work, deletion of the Hippo component Sav in mouse and pig cardiomyocytes with established ischemic cardiomyopathy and heart failure (HF) reverses HF and improves heart function due to increased nuclear YAP and activation of YAP target genes. In addition, we discovered that the dystrophin-glycoprotein complex sequesters YAP in adult cardiomyocytes. Hence, our ongoing objective is to unveil the mechanism(s) of Hippo-mediated cardiac cell regeneration. One of these mechanisms is to regulate cytoskeletal remodeling and protrusion formation. We also found that Yap makes chromatin more accessible for the expression of fetal genes, thereby promoting reprogramming of somatic cells into a primitive, fetal-like proliferative state. We work extensively with ischemia-reperfusion–induced myocardial infarction mouse and pig models and recently demonstrated that locally delivered gene therapy to inhibit Hippo in border zone cardiomyocytes is the first example of bona fide tissue renewal therapy. These studies have improved the understanding of the regulatory mechanisms that control cardiac development, disease and regeneration with the long-term goal of developing novel HF therapies.