Epicardium is one of the important components of the heart and plays a critical role in cardiogenesis. Moreover, further studies have shown that epicardium contributes to post-injury heart regeneration. After heart injury, epicardium secretes various signaling factors, regulating the cardiomyocyte proliferation and neovascularization. In addition, epicardium differentiates into many kinds of cells which take part in the heart repair in response to heart damage. In this review, we summarize recent progress on epicardial function, related signaling pathways and the potential clinical application, and provide a reference for future studies in epicardium and heart regeneration.