Myelodysplastic syndrome (MDS) is composed of a diverse spectrum of hematopoietic stem cell malignancies characterized by ineffective blood cell production. Many MDS patients are dependent on red blood cell (RBC) transfusions for symptomatic management of refractory anemia. Iron overload ensues when the iron acquired from transfused RBCs exceeds body storage capacity, thereby raising the risk for end organ damage. This is of greatest concern in patients with lower-risk MDS whose expected survival is measured in years. Transfusion dependence is associated with shorter survival and an increased risk for progression to acute myeloid leukemia (AML) in transfusion-dependent patients. Application of recent advances in the treatment of MDS can reduce or eliminate the need for transfusions, thus minimizing the risk of iron overload. Case control studies, prospective surveys, and phase II studies indicate that iron chelation therapy reduces iron load as measured by changes in serum ferritin and may prolong overall survival. Iron chelation strategies include oral agents such as deferasirox (Exjade, Novartis Pharmaceuticals Corp, East Hanover, NJ), deferiprone (Ferriprox, Apotex Europe BV, Leiden, the Netherlands) and, for those patients who are intolerant of or for whom oral therapy is ineffective, parenteral administration of deferoxamine (Desferal, Novartis). This review presents the data related to iron overload in MDS, including its prevalence, diagnosis, clinical impact, and management.