A greatly expanded understanding of the biology of endogenous erythropoietin (EPO) has emerged since the early 1990s. Originally viewed as the renal hormone dedicated to erythrocyte production, it is now clear that EPO is produced locally by many other tissues in response to physical or metabolic stress. In its autocrine-paracrine roles, EPO mediates preconditioning (ischemic tolerance) and specifically limits the destructive potential of tumor necrosis factor alpha and other proinflammatory cytokines in the brain, heart, kidney, and other tissues. As local production of EPO is generally suppressed following injury, administration of exogenous EPO has been a successful therapeutic approach in preclinical and clinical studies, for example, following ischemia-reperfusion and toxin-induced renal injuries, and in human stroke. The therapeutic time window of tissue protection by EPO is typically very wide in experimental models, showing effectiveness when administered before, during, or after an insult and raising optimism for a high clinical potential. Although there is progress in understanding the signaling pathways responsible for EPO's tissue-protective actions that are similar to, but not as redundant as, those employed for erythrocyte maturation, much work remains to be carried out. Experimental observations also suggest the existence of EPO receptor (EPOR) isoforms mediating EPO's diverse biological activities and have identified a tissue-protective receptor complex consisting of the EPOR and the beta common receptor (CD131) subunit that is also employed by granulocyte-macrophage colony-stimulating factor, interleukin-3 and interleukin-5. Successfully engineered analogues of EPO that selectively activate tissue protection without stimulating hematopoiesis confirm the concept of a tissue-protective receptor and have significant potential utility in the investigational and therapeutic arenas.