Epicardial resident stem cells are known to differentiate into cardiomyocytes during cardiac development, amongst other cell types. Whether epicardium-derived progenitor cells (EPDCs) retain this plasticity in the adult heart has been the topic of heated scientific debate. Priming with thymosin beta 4, a peptide which has been suggested to be critical for cardiac development and to have cardio-protective properties, was recently shown to induce differentiation of EPDCs into cardiomyocytes in a small animal model of myocardial infarction. This finding is in stark contrast to another recent study in which thymosin beta 4 treatment following myocardial infarction did not induce cardiomyocyte differentiation of EPDCs. While EPDCs seem to exhibit overall cardio-protective effects on the heart following myocardial infarction, they have not been shown to differentiate into cardiomyocytes in a clinically relevant setting. It will be important to understand why the ability of one therapeutic agent to induce cardiomyocyte differentiation of EPDCs seemingly depends on a single variable, i.e. the time of administration. Furthermore, in light of a recent report, it appears that thymosin beta 4 may be dispensable for cardiac development.