ABSTRACT Heart failure is a costly and deadly disease affecting over 5 million Americans. The inability of the adult mammalian heart to regenerate following injury lies at core of the pathophysiology of heart failure. We recently showed that the neonatal mammalian heart is capable of complete regeneration in the first few days of life following various types on injury. Despite the important implications to human heart disease, it is remains unclear whether larger mammals or humans have this regenerative potential, a phenomenon that would have significant mechanistic and therapeutic implications for pediatric as well as adult heart disease. In the current proposal, we will examine whether a similar cardiac regenerative potential exists in large mammals, outline the duration of this regenerative window, and decipher the regulators that controls myocyte cell cycle. In addition, we will examine whether we can modify these key regulators to control the myocytes cell cycle for remuscularization of hearts with myocardial infarction.