Tumor hypoxia, mostly resulting from poor perfusion and anemia, is one of the key factors in inducing the development of cell clones with an aggressive and treatment-resistant phenotype that leads to rapid progression and poor prognosis. Studies in patients with solid tumors suggest that there is a range of hemoglobin (Hb) concentrations that is optimum for tumor oxygenation. When used to achieve an Hb level within this range, erythropoiesis-stimulating agents (ESAs) can be expected to increase tumor oxygenation, and this may favorably influence sensitivity to treatment as well as quality of life. There is no robust evidence that ESAs, when used as indicated, have a negative effect on survival in patients with solid tumors. When used outside the indications recommended, the rise in Hb level that results may reduce tumor blood flow and tissue oxygenation because of a raised viscosity within the abnormal tumor microvasculature. In the current situation, it remains important to use ESAs within the approved indications and according to treatment guidelines such as those developed by the European Organization for Research and Treatment of Cancer.