Traditionally, erythropoietin (EPO) is described as a hematopoietic cytokine, regulating proliferation and differentiation and survival of the erythroid progenitors. The recent finding of new sites of EPO production and the wide spread distribution of EPO receptors (EPO-R) on endothelial cells, cardiomyocytes, renal cells as well as the central and peripheral nervous system raised the possibility that EPO may exert pleiotropic actions on several targets. Indeed studies (mainly preclinical) have documented protective, non-hematopoietic, abilities of EPO in a variety of tissue. However, the data obtained from clinical studies are more skeptical about these properties. This article provides a comprehensive overview of EPO and its derivatives.