Patients with lower-risk myelodysplastic syndromes (MDSs), usually defined as having an International Prognostic Scoring System score of 1.0 or less, and/or <5% myeloblasts, comprise the majority of newly diagnosed and established MDS patients and have a survival measured in years. Most will eventually require therapy for their disease, usually when MDS-related symptoms or transfusion requirements accelerate and outweigh potential drug-related toxicities. The decision of when to initiate therapy is far from straightforward. Erythropoiesis stimulating agents yield responses in up to 40% of appropriately selected patients, while disease-modifying drugs, including lenalidomide, azacitidine, decitabine and anti-thymocyte globulin, can evoke responses as high as 67% in patient subgroups. Newer therapies hold the promise of activity in patients who have failed standard regimens.