Recent advances in the understanding of acute myeloid leukemia (AML) and myeloid leukemogenesis have begun to narrow the focus of therapy to specific molecular aberrations that characterize subsets of this disease. Rather than embracing "one-fits-all" cytarabine-based chemotherapy as a standard approach for all patients, ongoing clinical research in AML focuses on drugs that target unique genomic aberrations, protein structure/functional alterations, or dysregulated cellular pathways that are specific for molecular subgroups of patients. Epigenetic modifications causing gene transcriptional repression have been associated with malignant transformation and are intriguing new targets in the treatment of AML. In contrast to genetic deletions causing irreversible loss of gene function, epigenetic gene silencing mediated by DNA methylation and histone deacetylation can be reversed via pharmacologic inhibition of DNA methyltransferases and histone deacetylases, respectively. When this occurs, normal patterns of gene expression, hematopoietic differentiation, and apoptosis may be restored and disease response obtained. In this review, we focus on the clinical applicability of epigenetic targeting in the treatment of patients with AML.