Since the regenerative capacity of the adult mammalian heart is limited, cardiac injury leads to the formation of scar tissue and thereby increases the risk of developing compensatory heart failure. Stem cell therapy is a promising therapeutic approach but is facing problems with engraftment and clinical feasibility. Targeting an endogenous stem cell population could circumvent these limitations. The epicardium, a membranous layer covering the outside of the myocardium, is an accessible cell population which plays a key role in the developing heart. Epicardial cells undergo epithelial to mesenchymal transition (EMT), thus providing epicardial derived cells (EPDCs) that migrate into the myocardium and cooperate in myocardial vascularisation and compaction. In the adult heart, injury activates the epicardium, and an embryonic-like response is observed which includes EMT and differentiation of the EPDCs into cardiac cell types. Furthermore, paracrine communication between the epicardium and myocardium improves the regenerative response. The significant role of the epicardium has been shown in both the developing and the regenerating heart. Interestingly, the epicardial contribution to cardiac repair can be improved in several ways. In this review, an overview of the epicardial origin and fate will be given and potential therapeutic approaches will be discussed.