Acute myeloid leukemia (AML) is the most common leukemia diagnosed in adults and curative treatments remain currently a great challenge. AML occur in about 60% of patients over 60 years with unsatisfactory survival results, which have not improved significantly over the last two decades, in spite of improved supportive care. Global genomic instability is the hallmark of the disease, leading to chromosomal/molecular alterations, proliferative advantage and clonal heterogeneity. Epigenetic deregulation of gene expression is considered as a consequence and/or the initiating cause of this instability and DNA methylation is one of the most commonly occurring epigenetic events in this setting. The plasticity of the epigenome, compared to the conserved status of the genome, designed it as a therapeutic target especially in AML. Among novel therapeutic agents, the availability of compounds targeting epigenetic modifiers offers the opportunity to have new therapeutic insights with improvement of outcome, especially in older patients, while reducing toxicity. We reviewed herein some of the epigenetic mechanisms involved in normal hematopoiesis, which may be deregulated in AML, and therapeutic potentials of cell re-programming.