The epicardium is composed of a single cell layer that encapsulates the heart during embryogenesis. The epicardium also serves as a rich source of mesenchymal cells and growth factors that support coronary vasculature development. Although the function of the epicardium is invariably linked to the growth of the primitive coronary plexus, the cellular and molecular mechanisms that regulate the function of the epicardium remain unclear. To facilitate the identification of the epicardium’s role in embryonic angiogenesis, our lab utilizes transgenic mouse models and single-cell transcriptomic sequencing to discover novel epicardium-directed guidance cues required for arterio-venous specification and maturation of endothelial cells. As compared to the fetal heart, the adult myocardium is unable to undergo angiogenesis in response to ischemic injury, which ultimately leads to cardiac functional decline. By using information acquired from our studies during development, we are investigating the effects of pro-angiogenic factors from the epicardium to promote angiogenesis and repair after ischemic injury in the adult heart.