A hallmark of acute myeloid leukemia (AML) is epigenetic dysregulation, which is initiated by recurrent translocations and/or mutations in transcription factors and chromatin regulators. This manifests as a block in myeloid differentiation and an increase in malignant self-renewal. These common features of AML have led to widespread optimism that epigenetic therapies would dramatically change the natural history of this disease. Although preclinical studies with these drugs fueled this optimism, results from early clinical trials have offered a more sobering message. Here, we provide an overview of epigenetic therapies that are currently approved by therapeutic regulatory authorities across the world and those undergoing early-phase clinical trials. We also discuss the conceptual and molecular factors that may explain some of the disparity between the bench and bedside, as well as emerging avenues for combining the current generation of epigenetic therapies with other classes of agents and the development of novel epigenetic therapies. With further research and development of this exciting class of drugs, we may finally be able to dramatically improve outcomes for patients afflicted with this aggressive and often incurable malignancy.