The use of erythropoietin (EPO) and intravenous (IV) iron as bloodless therapeutic modalities is being explored in the current era of restrictive transfusion strategies and perioperative blood management. It is unclear, however, whether the evidence in the literature supports their safety and efficacy in reducing perioperative red cell transfusions. Adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines, we conducted a systematic review to evaluate their use in a variety of perioperative settings. We performed a literature search of English articles published between July 1997 and July 2012 in MEDLINE via PubMed, The Cochrane Library, and CINAHL. Only studies with a comparator group were eligible for inclusion. Twenty-four randomized controlled trials (RCTs) and 15 nonrandomized studies were included in the final review. Using the Cochrane risk of bias tool, 8 RCTs were assessed to be at low risk for methodological bias. Of these, however, only 4 RCTs were adequately powered to detect a reduction in transfusion rates. Patients with preoperative iron deficiency anemia may have an earlier and more robust hemoglobin recovery with preoperative IV iron therapy than with oral iron supplementation. A short preoperative regimen of EPO, or a single dose of EPO plus IV iron in the preoperative or intraoperative period, may significantly reduce transfusion rates (number needed to treat to avoid any transfusion ranged from 3 to 6). With regard to the safety of erythropoietin-stimulating agent therapy, IV iron appears to be as well tolerated as oral iron; however, the incidence of severe anaphylactic-type reactions attributable to IV iron is difficult to estimate in prospective trials because of its relatively infrequent occurrence. Furthermore, EPO may increase the risk of thromboembolism in spinal surgery patients who receive mechanical antithrombotic prophylaxis in the perioperative period so pharmacological thromboprophylaxis is advised. Future low risk of bias, adequately powered prospective efficacy, and safety trials in various surgical settings that traditionally require red cell transfusions would be required to make evidenced-based conclusions about the clinical significance of erythropoietin-stimulating agent as a transfusion avoidance strategy in perioperative blood management.