Over the past several years, increasing attention has been focused on understanding signaling pathways that control key events during midgestational heart development. During this period of development, the heart tube transforms into a functioning organ that must maintain its own blood supply and grow and respond to the physiologic needs of the organism. A critical event that occurs during midgestational heart development is the formation of the epicardium, which functions as a source of cells and as a signaling center that regulates myocardial growth and coronary vascular development. This review will describe our understanding of the role and the mechanism by which the epicardium governs these developmental events, primarily as a result of studies in the mouse. We focus on two key growth factor pathways: fibroblast growth factor and Hedgehog signaling.