Erythropoietin (EPO) is an endogenous hormone produced in the kidney that regulates red blood cell production within the body. Since the cloning and first clinical introduction of recombinant erythropoietin (epoetin) in the late 1980s indications and usage of epoetin have expanded significantly. It is estimated that as many as one third of patients with substantial anemia (hemoglobin less than 10.0 g/dL) resulting from chemotherapy for cancer are treated with epoetin. Though use of epoetin may avoid the inconvenience and infectious risk of blood transfusions, it is expensive and its benefit in some clinical scenarios has been modest. Like many new technologies, strong evidence suggesting situations where the benefit is high has lagged behind its adoption by patients and practitioners. As well, epoetin is expensive and third party payers do not always reimburse it. Research suggests there is considerable variation in epoetin usage in practice. To provide guidance to hematology/oncology specialists regarding use of epoetin, the American Society of Hematology (ASH) and the American Society of Clinical Oncology (ASCO) proposed that the Agency for Healthcare Research and Quality (AHRQ) fund an evidence review by one of the Evidence-based Practice Centers (EPC) that would be used to develop evidence-based guidelines for members of the society. This review highlights principles of evidence-based medicine, distills and appraises the evidence in the published literature that supports the use of epoetin, and presents evidence-based recommendations for use of epoetin in situations where benefit is substantiated by high-quality studies. As well, this review addresses some of the difficulties of performing clinical research in this area, provocative research findings that will require further study, and suggestions regarding epoetin in those areas where further strong evidence has yet to be developed.