This chapter discusses treatment of myelodysplastic syndrome (MDS). When treating newly diagnosed MDS, therapy should be tailored to each patient according to the specific risk profile, and whenever possible, patients should be treated on a clinical trial. Erythropoiesis-stimulating agents are an appropriate initial treatment for anemia in lower-risk MDS patients. The US Food and Drug Administration has approved lenalidomide for lower-risk MDS patients. Lenalidomide treatment of higher-risk MDS with del(5q) should be considered investigational, and the authors’ practice uses lenalidomide exclusively in lower-risk patients. Those patients who failed to achieve a response to lenalidomide appeared to have a higher rate of acute myeloid leukemia progression compared to those who responded. This chapter discusses lower-risk, intermediate-risk, and higher-risk patients, as well as therapy-related MDS and treatment failure.