The epicardium, the tissue layer covering the cardiac muscle (myocardium), develops from the proepicardium, a mass of coelomic progenitors located at the venous pole of the embryonic heart. Proepicardium cells attach to and spread over the myocardium to form the primitive epicardial epithelium. The epicardium subsequently undergoes an epithelial-to-mesenchymal transition to give rise to a population of epicardium-derived cells, which in turn invade the heart and progressively differentiate into various cell types, including cells of coronary blood vessels and cardiac interstitial cells. Epicardial cells and epicardium-derived cells signal to the adjacent cardiac muscle in a paracrine fashion, promoting its proliferation and expansion. Recently, high expectations have been raised about the epicardium as a candidate source of cells for the repair of the damaged heart. Because of its developmental importance and therapeutic potential, current research on this topic focuses on the complex signals that control epicardial biology. This review describes the signaling pathways involved in the different stages of epicardial development and discusses the potential of epicardial signals as targets for the development of therapies to repair the diseased heart.