The nuclear protein high-mobility group box 1 (HMGB1) has been largely characterized for its role in inflammation. However, HMGB1 released by inflammatory cells, as well as by necrotic cells, may also act as a signal of tissue damage and participate in tissue repair by recruiting stem cells to the injury site. The emergence of this function has focused the interest on HMGB1 as a molecule with an active role in tissue regeneration. We recently demonstrated that HMGB1 administration in a mouse model of myocardial infarction activates cardiac stem cells and promotes their differentiation into cardiomyocytes. The regenerative effect results in the improvement of cardiac function. In this review, we highlight the beneficial role of HMGB1 and discuss growth factor-based therapeutic approaches for the treatment of myocardial infarction.