The mammalian heart loses its regenerative capacity during early postnatal stages; consequently, individuals surviving myocardial infarction are at risk of heart failure due to excessive fibrosis and maladaptive remodeling. There is an urgent need, therefore, to develop novel therapies for myocardial and coronary vascular regeneration. The epicardium-derived cells present a tractable resident progenitor source with the potential to stimulate neovasculogenesis and contribute de novo cardiomyocytes. The ability to revive ordinarily dormant epicardium-derived cells lies in the identification of key stimulatory factors, such as Tβ4, and elucidation of the molecular cues used in the embryo to orchestrate cardiovascular development. myocardial infarction injury signaling reactivates the adult epicardium; understanding the timing and magnitude of these signals will enlighten strategies for myocardial repair.