Abstract Myelodysplastic syndromes (MDS) are a diverse group of myeloid disorders, with patients being at risk for cytopenias or progression to acute myeloid leukemia. Several classification and prognostic scoring systems have been developed. High-intensity treatments are not appropriate for all patients. Two demethylating agents, azacitidine and decitabine, are approved for treatment of MDS, though many patients do not derive long-term benefit and eventually progress. Deacetylase inhibitors have emerged as novel treatment candidates based on mechanistic rationale and preliminary data. This article reviews existing data on MDS treatment and discusses the rationale and potential for combination with deacetylase inhibitors.