The importance of epigenetic aberrations in the pathogenesis of leukemias has been revealed by recurrent gene mutations that highlight epigenetic pathways as well as by the clinical success of therapies like 5-azacytidine and decitabine that work through epigenetic mechanisms. However, precise mechanisms of how gene mutations lead to leukemias and how epigenetic therapies induce clinical remissions are elusive. Current scientific inquiries that take advantage of techniques that can distinguish among the various covalent cytosine modifications at single base resolution are likely to shed light on the ways epigenetic pathways drive leukemogenesis as well as how the hypomethylating drugs induce clinical remissions. The hope is that these studies will also reveal which patients are likely to respond to epigenetic therapies. Thus, the future is likely to bring a new wave of diagnostic and prognostic tools that probe the epigenomics of leukemia to help clinicians in their management of patients.