<p>Although we are just beginning to understand the mechanisms that regulate the epigenome, aberrant epigenetic programming has already emerged as a hallmark of hematologic malignancies including acute myeloid leukemia (AML) and B-cell lymphomas. Although these diseases arise from the hematopoietic system, the epigenetic mechanisms that drive these malignancies are quite different. Yet, in all of these tumors, somatic mutations in transcription factors and epigenetic modifiers are the most commonly mutated set of genes and result in multilayered disruption of the epigenome. Myeloid and lymphoid neoplasms generally manifest epigenetic allele diversity, which contributes to tumor cell population fitness regardless of the underlying genetics. Epigenetic therapies are emerging as one of the most promising new approaches for these patients. However, effective targeting of the epigenome must consider the need to restore the various layers of epigenetic marks, appropriate biological end points, and specificity of therapeutic agents to truly realize the potential of this modality.</p>