Erythropoietin (EPO) has firstly known to regulate cell proliferation and differentiation along the erythroid lineage. Recent studies have shown that EPO, a pleiotropic cytokine, is proangiogenic and exerts broad tissue-protective effects in diverse nonhematopoietic organs. A series of studies have documented the expression of EPO and EPO receptor (EPO-R) in various cancer cells. The presence of an autocrine-paracrine EPO/EPO-R system may associate with the potential for stimulation of tumor neoangiogenesis and tumor proliferation, inhibition of apoptosis, or modulation of sensitivity to chemoradiotherapy. The complex mechanism needs further research. Recombinant human erythropoietin (rh-EPO) has been widely used in clinic to treat malignancy-associated anemia. Clinical trials have documented the efficacy of rh-EPO in increasing hemoglobin levels, reducing red blood cell (RBC) transfusion requirements and improving quality of life in cancer patients. However, three randomized trials reported negative outcomes with rh-EPO, as patients in the rh-EPO arm fared worse than their placebo-treated counterparts with progression-free survival. This review described EPO and EPO-R biology, focusing on the expression, pleiotropic function and mechanism on nonhematopoietic tissues especially on cancer cells.