The recently approved drugs 5-azacitidine (5AC) and 5-aza-2'-deoxyazacytidine (DAC) are in wide clinical use for the treatment of myelodysplastic syndrome (MDS) of all types and chronic myelomonocytic leukemia (CMML). These agents were developed based upon an understanding of the importance of epigenetic changes in malignancy, and they have been evaluated in randomized clinical trials, which demonstrate response rates between 20% and 40% in patients for whom no previous standard of care was available. As understanding of the epigenetic changes characteristic of the malignant phenotype improves, we are able to target other regulators of chromatin conformation that contribute to aberrant gene transcription and dysregulated cell growth. The histone deacetylase (HDAC) inhibitors belong to one class of therapeutics developed using this paradigm. Although responses using HDAC inhibitors alone in MDS have been modest, robust preclinical data drive clinical trials in which they are utilized in combination with DNA methyltransferase (DNMT) inhibitors. Combination therapy offers the possibility of hematologic improvement and remission to myelodysplastic patients with previously untreatable disease.