The management of cancer-related anemia with erythropoietic agents presents many unresolved issues. We reviewed the literature relating to epoetin alfa (Eprex)/Epypo); Ortho Biotech/Janssen-Cilag, High Wycombe, United Kingdom, http://www.orthobiotech.co.uk; Procrit); Ortho Biotech Products, L.P., Bridgewater, NJ, http://www.orthobiotech.com), epoetin beta (NeoRecormon); Hoffman-La Roche, Basel, Switzerland, http://www.roche.com), and darbepoetin alfa (Aranesp); Amgen Inc., Thousand Oaks, CA, http://www.amgen.com) highlighting the results of published clinical trials, safety, and cost-effectiveness. Studies were identified through MEDLINE and the bibliographies of relevant articles. Epoetin alfa, epoetin beta, and darbepoetin alfa have differing pharmacokinetic and pharmacodynamic profiles. They are all effective at reducing transfusion requirements and improving health-related quality-of-life parameters, irrespective of tumor response. A direct comparison between epoetin alfa and darbe poetin alfa is based on limited evidence, which does not allow definitive conclusions about relative efficacy and cost-effectiveness. No predictive factors for response to erythropoietic agents have been validated in prospective trials. The most consistent adverse events are thrombotic and may occur irrespective of an increase in hemoglobin. Recent research indicates that the erythropoietin receptor is expressed in several cancer cell lines, raising the concern of possible stimulation of tumor cell growth by these drugs. Studies on the cost-effectiveness of erythropoietins, particularly compared with transfusion therapy, have been challenging to conduct and analyze and have generated ambiguous results. The use of erythropoietins needs to be optimized in terms of cost-effectiveness, and issues surrounding safety need to be clarified. A stronger methodology for clinical studies and the design of new, randomized, clinical trials is a major priority.