Several growth factors have been shown to protect the cardiomyocyte from the detrimental effects of acute ischemia-reperfusion injury, through the activation of a variety of cell-surface receptors and the subsequent recruitment of a number of intracellular signal transduction pathways. Among these growth factors, hepatocyte growth factor (HGF), also named as scatter factor, acts by recruiting the phosphatidylinositol 3-kinase (PI3K)-Akt signal transduction pathway, linked to cardioprotection, at the time of myocardial infarction and myocardial reperfusion. HGF has been reported to increase in the early phase of myocardial infarction, and has been shown to have mitogenic, angiogenic, antiapoptotic and antifibrotic activities in cardiac myocytes and endothelial cells. Also, endogenous HGF may play an important role in the regeneration of endothelial cells and cardiomyocytes by promoting angiogenesis and inhibiting apoptosis during remodeling of the ischemic myocardium. Thus, HGF has the potential to emerge as a cardioprotective agent for the treatment of several pathological cardiac conditions. Here we review the role of HGF with respect to its ability to confer direct myocardial protection in the setting of ischemia-reperfusion injury, focusing on the main underlying signaling pathway involved. © 2013 Italian Federation of Cardiology.