EPO uses receptor isoforms for signaling. A homodimer receptor (EPOR)2 is formed by the spontaneous self-assembly of EPOR monomers and mediates erythro-poiesis (left). The receptor-ligand stoichiometry is 2:1 for EPOR and EPO, respectively. The hematopoietic receptor is characterized by a high affinity for EPO and requires constant, low circulating concentrations of EPO to maintain adequate erythrocyte production. Other biological activities controlled by (EPOR)2 are those associated with preservation of red cell mass in the setting of hemorrhage. These functions include induction of a prothrombotic state by activation of vascular endothelium adhesion molecules and accelerated maturation of megakaryocytes, as well as stimulation of vascular smooth muscle leading to shunting of blood from noncritical tissues. All of these activities serve to minimize blood loss. In contrast, available evidence supports the existence of a different receptor for tissue protection (middle) that involves assembly of EPOR and βCR subunits, as well as other receptor subunits (right; for example, VEGFR2) in certain tissues. On the basis of analogy to the GM-CSF receptor, the stoichiometry may be in a 2:2:2 ratio for EPO, EPOR and βCR. The TPR is characterized by a lower affinity for the endogenous ligand EPO and requires only brief receptor occupancy to initiate long-lasting biological effects. Because high doses of EPO are required for TPR activation, tissue protection by exogenous EPO is unavoidably accompanied by these potential serious adverse consequences. To circumvent these potential problems, analogs of EPO have been engineered that lack hematopoietic potency but retain tissue-protective activity. This strategy provides tissue protection while avoiding the significant potential side effects of using EPO itself.