The ability of the DNA methyltransferase inhibitors (DNMTi) to induce terminal differentiation in fibroblasts was first noted by Taylor and Jones in 1979; Silverman and Holland reported hematologic improvement in patients with myelodysplastic syndrome (MDS) in 1993. That azacitidine improves survival in patients with high-risk MDS and acute myeloid leukemia with MDS features compared with a combined comparator group of supportive care, low-dose cytarabine, and intensive cytarabine plus anthracycline, while inducing trilineage normalization in approximately 15% of patients makes the development of more potent, more specific drugs that behave like azacitidine imperative. The question is, how do the azanucleosides behave?