Ischemic heart disease is the most common cause of heart failure and is among the leading causes of mortality worldwide. Therapies used for the treatment of this disease aim to restore blood flow to severely narrowed or occluded coronary arteries by either catheter-based or surgical means. Although these strategies prove efficacious for many patients, a substantial number of individuals fail to improve following these procedures. Recently, a noninvasive strategy has been proposed, focusing on the use of endogenous growth factors that trigger the growth of new coronary arteries. Using the developing heart as a model, several groups have identified some of the key pathways that not only govern the development of the coronary vascular system but also promote the growth of the adult coronary vasculature. Here, we review the major morphological events and signaling cascades that mediate the formation of the coronary vasculature in the embryo. We further describe the mechanism by which many of these same pathways also regulate the adult coronary vasculature and their potential use in the treatment of ischemic heart disease.