Erythropoietin-stimulating agents (ESAs) were originally designed to replace endogenous erythropoietin in patients with anemia secondary to renal failure. Their use has subsequently been expanded to include patients with anemia of other causes, including cancer patients, in whom deficiency of erythropoietin, per se, is not the primary cause of anemia. Although early studies showed promise of ESA administration in reducing the need for transfusions and improving the quality of life in cancer patients, several large randomized clinical trials have recently shown a potential detrimental effect of ESA administration on tumor progression and survival in these patients. These studies have called into question the safety of ESAs as supportive therapy in patients being treated for oncologic conditions. However, numerous questions remain to be addressed regarding the design of these studies, the effect of various targeted hemoglobin levels, and the potential biologic mechanisms proposed to explain promotion of tumor progression and reduced survival.