Normal hematopoiesis is sustained by multipotent hematopoietic stem cells (HSC) that are able to both self-renew and give rise to differentiated cells throughout the lifetime of an individual. These cell fate decisions are characterized by changes in transcriptional cell states, mediated by heritable epigenetic processes, notably post-translational modifications of nucleosome proteins and direct methylation of DNA. These changes in chromatin structure are coordinated by specific “writer” and “eraser” enzymes and specifically bound by epigenetic “readers”. Acute myeloid leukemia (AML) arises as a result of dysregulation of this ordered transcriptional progression, resulting in an aggressive disease characterized by a block in differentiation and increased proliferation. Moreover, mutations of transcriptional regulators and chromatin modifiers are recurrent in AML. Importantly, the resultant epigenetic changes are plastic and clinical evidence suggests that targeting epigenetic alterations can reset pathological transcriptional programs, with clinically-relevant outcomes. In this review, we will outline recent progress in the development of agents that target chromatin in AML.