Myocardial fibrosis is the main pathological process during the post-myocardial infarction phase (post-MI), which is characterized by the imbalance between extracellular matrix (ECM) synthesis and degradation, in which fibroblasts and myofibroblasts play an important role. Replacement fibrosis can reduce the further expansion of the infarction area, maintain ventricular integrity, and prevent ventricular wall rupture after MI. However, reactive fibrosis in the infarct border zone and in the remote uninjured myocardium leads to altered chamber compliance and increased ventricular stiffness, thereby compromising cardiac output. Therefore, an ideal therapy for MI-induced cardiac injury would combine the inhibition of reactive fibrosis (and other remodeling processes) in non-infarct areas with the induction of the regeneration of the infarcted myocardium to improve heart function.