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Cardiovascular diseases, particularly myocardial infarction, remain a leading cause of mortality globally, primarily due to the adult heart's limited regenerative capacity. Recent discoveries have highlighted the epicardium, a mesothelial layer surrounding the heart, as a critical player in cardiac repair and regeneration. During development, the epicardium plays a central role in heart formation by providing progenitor cells, structural components, and paracrine signals. Emerging evidence indicates that this developmental potential can be reactivated in the adult heart following injury. Upon activation, epicardial cells undergo epithelial-to-mesenchymal transition, proliferate, and secrete a range of paracrine factors that influence angiogenesis, inflammation resolution, and extracellular matrix remodeling. This review explores the mechanisms underlying epicardial activation, its contributions to heart development and myocardial repair, and its therapeutic potential. We discuss small molecule modulators, gene therapy, cellular therapies, and biomaterial-based approaches that aim to harness the regenerative capacity of the epicardium. These approaches, which move beyond scar tissue formation to possible regeneration, have the potential to transform the landscape of cardiac regenerative medicine. Despite promising preclinical results, however, challenges such as interindividual variability, incomplete differentiation of epicardial-derived cells, and delivery constraints must be addressed. Advances in single-cell technologies, biomaterial engineering, and translational research are paving the way for personalized and effective epicardium-based therapies. By redefining the role of the epicardium in cardiac biology, epicardial activation offers a novel paradigm for treating ischemic heart disease and heart failure.