Heart diseases are a very common health problem in developed as well as developing countries. In particular, ischemic heart disease and heart failure represent a plague for the patients and for the society. Loss of cardiac tissue after myocardial infarction or dysfunctioning tissue in nonischemic cardiomyopathies may result in cardiac failure. Despite great advancements in the treatment of these diseases, there is a substantial unmet need for novel therapies, ideally addressing repair and regeneration of the damaged or lost myocardium. Along this line, cardiac cell based therapies have gained substantial attention. Three main approaches are currently under investigation: stem cell therapy with either embryonic or adult stem cells; generation of patient-speciﬁcinduced pluripotent stem cells; stimulation of endogenous regeneration trough direct reprogramming of ﬁ broblasts into cardiomyocytes, activation of resident cardiac stem cells or induction of native resident cardiomyocytes to reenter the cell cycle. All these strategies need to be optimized since their efficiency is low. t has recently become clear that cardiac signaling and transcriptional pathways are intimately intertwined with microRNA molecules which act as modulators of cardiac development, function, and disease. Moreover, miRNA also regulates stem cell differentiation. Here we describe how miRNA may circumvent hurdles that hamper the ﬁeld of cardiac regeneration and stem cell therapy, and how miRNA may result as the most suitable solution for the damaged heart.