Myelodysplastic syndrome (MDS) is not a single disease, but a collection of hematopoietic disorders that require newer strategies. Currently, azacitidine, decitabine, and lenalidomide are approved by the US Food and Drug Administration for the treatment of MDS. A recent study demonstrated an improved overall survival (24.4 months vs 15 months) in high-risk MDS patients receiving azacitidine plus best supportive care vs conventional care which has resulted in an updated label for this product. Conventional care consisted of supportive care alone or either low-dose ara-C or standard chemotherapy plus best supportive care. While these data are encouraging, newer agents such as vorinostat, MGCD0103, MS-275, and tipifarnib are currently being studied as monotherapy or in combinations with approved treatments for MDS. The goal of combining pharmacotherapy, such as the combination of DNA methylation inhibitors and histone deacetylase inhibitors, in the management of MDS is to increase the response rates and decrease the toxicities associated with treatment. Clinical experience in the use of combination products has given practitioners the empirical knowledge necessary to better treat patients with MDS. Utilizing convergent or complementary molecular mechanisms with in vitro or in vivo evidence of synergy is a fresher and maybe a more efficacious approach to combination therapy.