Myocardial damage is frequently occurring upon a prolonged period of ischemia, although subsequent reperfusion as standard therapy is established. Among the pleiotropic causes of ischema-reperfusion injury, loss of cardiomyocytes, microcirculatory disturbances, and postischemic inflammation have been frequently observed. Current clinical cell therapy after acute myocardial mostly aims at neovascularization and enhancement of tissue repair, whereas acute cardioprotection after ischemia and reperfusion has rarely been studied. Recently, embryonic endothelial progenitor cells (eEPCs) have been found to provide cardioprotection against acute ischemia-reperfusion injury (24 hours) in a preclinical pig model. The paracrine effect of eEPCs was mimicked by regional application of a single, highly expressed protein, Thymosin beta4. This review focuses on underlying mechanisms of acute cardioprotection provided by eEPCs and, in particular, Thymosin beta4.