Epicardium, the outer epithelial layer of the heart forming from extracardiac primordium, plays a fundamental role in myocardial embryogenesis by generating epicardial-derived cells (cardiac fibroblasts, mesenchymal cells, vascular smooth muscle cells). In the adult heart, epicardium occurs as a mesothelial layer, which, in injured heart, recalls its “embryonic program” and transforms into mesenchymal cells contributing, by such a way, to myocardial reparation. This process is facilitated by hypoxic conditions arising during injury. In general, regulation of this process may be a potential methodology for treatment of cardiovascular diseases.