Epigenetic regulation is known to affect gene expression, and recent research shows that aberrant DNA methylation patterning may play a role in leukemogenesis. All leukemias display aberrant distribution of cytosine methylation, which is most notably distributed in specific and distinct signatures in acute myeloid leukemia (AML). These signatures reflect leukemic mechanisms and have clinical and prognostic significance. Compared with genetic lesions in AML, epigenetic lesions appear to be more frequent and recurrent.