Anemia is the most frequent peripheral cytopenia observed in myelodysplastic syndromes (MDS) and has been recognized among the most important factors affecting the outcome of patients with MDS. In patients who are not candidates for potentially curative approaches, therapeutic options for symptomatic anemia include red blood cell (RBC) transfusion and iron chelation, hematopoietic growth factors, immunosuppression, immune-modulatory drugs, and hypomethylating agents. In about 40% of patients, regular RBC transfusions are the only therapeutic option that can be offered. The onset of a regular transfusion requirement significantly worsens the survival of patients with MDS. Transfusion-dependent patients invariably develop secondary iron overload. Elevated serum ferritin was proven to be associated with worse survival in transfusion-dependent patients, and recent data obtained using magnetic resonance imaging show both hepatic and myocardial iron accumulation in heavily transfused patients. According to evidence-based guidelines, patients with sideroblastic anemia, 5q- syndrome, or other forms of refractory anemia, in whom long-term transfusion therapy is likely, are recognized as the best candidates to receive iron chelation therapy. In addition, patients who are candidates for allogeneic stem cell transplantation might also benefit from chelation therapy because iron overload is associated with increased transplantation-related mortality. RBC transfusions and iron chelation are the mainstay of therapy for many individuals with MDS. However, critical issues remain to be clarified in order to optimize treatment, including the identification of target hemoglobin levels to prevent anemia-related morbidity and more accurate information on the effect of iron-mediated organ damage on the outcome of patients with MDS.