In recent years we have witnessed a transformation in care for patients with myelodysplastic syndromes (MDS) following approval by the US Food and Drug Administration of the first agents for treatment of the disease. Emerging evidence indicates that active treatment strategies modify the natural history of the underlying disease and hence lower the potential for leukemic transformation while prolonging survival. The methyltransferase inhibitor (MTI) azacitidine, in particular, has shown the capacity to extend survival in higher-risk disease in a post-approval phase III trial while demonstrating an improved risk/benefit profile in a new dosing schedule. By utilizing an MTI as a bridge to transplantation, allogeneic stem cell transplantation can now be postponed for appropriate candidates until a suitable donor is identified. Results of iron chelation studies indicate that the improved compliance of an oral iron chelator yields greater iron storage reduction with sustained suppression of the labile plasma form. The current active treatment paradigm for MDS incorporates the most recent strategies yielding improved disease outcomes and patient survival.