Erythropoietin (EPO) is not solely a hormone charged with regulating the proliferation and differentiation of erythroid cells. Indeed, EPO is synthesized locally by many cells, especially under conditions of stress or injury. In these paracrine/autocrine settings, EPO plays a crucial protective–restorative role, activating cytoprotection (e.g., in the brain, heart, and kidney), reducing inflammatory responses, preserving vascular integrity, and mobilizing stem cells, including proliferation and differentiation of endothelial progenitor cells. EPO administration prevents cardiac myocyte apoptosis and decreases infarct size in several studies using rodent models of myocardial infarction. Recently, some key steps of the signaling pathways by which EPO confers cardioprotection have been identified. The striking finding distilled from work by numerous independent investigators is that EPO mediates protection in the heart (as well as other tissues) by multiple pathways that are not redundant. The following actions proven to play a role in protection from acute cardiac injury can exert a beneficial effect in chronic heart failure (HF): (a) antiapoptotic effect, (b) mobilization of endothelial progenitor cells from bone marrow, and (c) anti-hypertrophic effects. The evidences discussed herein provide a strong basis for the ongoing clinical trials testing EPO in chronic HF.