Myelodysplastic syndrome, characterized by ineffective hematopoiesis and cytopenias, remains a lethal disease. Until recently, patients with myelodysplastic syndrome have been managed supportively with blood product transfusions and growth factors, until they succumb to infections, bleeding complications or transformation to acute leukemia. The discovery that epigenetic factors play an important role in cancer, and specifically in myelodysplastic syndrome, has led to the recent approval of several new therapies that will make a significant impact on this disease. Epigenetics refers to a number of biochemical modifications to chromatin that do not alter the primary DNA sequence, but play an important role in genomic regulation at the level of gene transcription. Epigenetic factors can be passed on from a cell to its progeny and can mimic traditional genetic lesions that are implicated in cancer. Unlike genetic abnormalities, however, epigenetic changes, such as DNA methylation or histone deacetylation, can be manipulated pharmacologically. Recently developed hypomethylating agents and histone deacetylase inhibitors have shown significant biological and clinical activity in myelodysplastic syndrome. These drugs have been well-tolerated by patients and have been shown to alter the course of this disease. In order to use these drugs optimally, however, we need to better understand the role of these epigenetic changes: how they contribute to the disease process, how we can use them to better select patients and how we can use combinations to target them more effectively.