More than 60 years after the first description of differentiation in cell culture and 40 years after the synthesis of 5-azacytidine, epigenetic therapies have been added to the anticancer armamentarium. DNA methyltransferase (DNMT) inhibitors such as 5-aza-2′-deoxycytidine or 5-azacytidine have been approved in myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML), whereas the histone deacetylase inhibitors (HDIs) including vorinostat, romidepsin, panobinostat, belinostat, and entinostat have been shown to be active in cutaneous and peripheral T-cell lymphoma. Although the range of malignancies in which monotherapy with DNMT inhibitors or HDIs are effective has been limited to date, the possibility remains that a broader spectrum of activity will be identified as combination studies are completed. Meanwhile, basic science has provided a steadily increasing understanding of the complexity of the epigenome, including the histone code and triggers for aberrant methylation, and their contribution to oncogenesis. As our basic understanding of the epigenetics of cancer increases, the number of potential therapeutic targets will also increase, offering more hope in the quest to treat cancer by normalizing the epigenome. This issue of CCR Focus is dedicated to understanding the clinical and translational aspects of epigenetics research.