Anemia is a deficiency in red blood cells or in the hemoglobin (Hb) levels that leads to a decrease in the transport capacity of oxygen in the blood, which can reduce tolerance in radiotherapy (RT) and chemotherapy. The relationship between anemia and hypoxia, however, is complex and influenced by multiple variables. Although the blood Hb values that might develop hypoxia in tumors were not described clearly, optimal oxygen pressure was accepted in patients with an Hb value of 12–14 g/dL. Erythropoietin is a glycoprotein, which acts via EPOR to stimulate the growth, to prevent apoptosis, and to induce differentiation of red blood cell precursors. RhuEPO-α and -β are classically administered subcutaneously three times per week at doses ranging from 150 to 300 IU/kg. Darbepoetin-α has been shown to exhibit a longer elimination half-life, thus allowing a once-weekly administration at the dose of 2.25 µg/kg. Side-effects related to rhuEPO include hypertension and thromboembolic events. RhuEPO can be used effectively in the treatment of anemia in patients with solid tumor being treated by RT or chemoradiotherapy. Furthermore, the use of rhuEPO has been demonstrated to have a sustained beneficial impact on quality of life in cancer patients. However, the role of combination of rhuEPO with external RT still remains inconclusive and several clinical trials have been pointed increased mortality in patients treated with rhuEPO. In this paper, the probable radiobiological effects of anemia in patients treated with RT, the beneficial and adverse effects of rhuEPO, and related studies are reviewed. Future directions for the use of rhuEPO are proposed.