Erythropoietin (EPO) is the major glycoprotein hormone regulator of mammalian erythropoiesis , and is produced by kidney and liver in an oxygen-dependent manner. The biological effects of EPO are mediated by the specific erythropoietin receptor (EPOR) on bone marrow erythroblasts, which transmits signals important for both proliferation and differentiation along the erythroid lineage. EPOR is a type 1 single-transmembrane cytokine receptor, and belongs to the homodimerizing subclass which functions as ligand-induced or ligand-stabilized homodimers. EPO binding to EPOR triggers auto- or trans-phosphorylation of a protein-tyrosine kinase JAK2 bound to the receptor cytosolic (CT) domain, and subsequently JAK2 activates a variety of intracellular signal substrates including Ras/MAPK, phosphatidylinositol 3-kinase and STAT transcription factors. The stimulated EPOR appears to function in erythroid cell survival through preventing the PCD, and is also suggested to play a neuroprotective role for its expression in mammalian brains. Aberrantly expressed EPOR is implicated in pathogenesis of various human diseases including erythroleukemia and familial erythrocytosis.