Cancer is now thought of as a fundamentally genetic disease, in that changes in the genome result in aberrant gene expression of oncogenes and tumor suppressor genes to promote oncogenesis. However, with our increasing knowledge of gene regulation, it is becoming obvious that changes in nucleotide sequence are not the sole mechanism for eliciting changes in transcription. An additional layer of regulation of gene expression, called epigenetics, is now being realized as increasingly important in oncogenesis. Epigenetics is defined as non-sequence based changes in chromatin that elicit changes in gene expression that are propagated through mitosis and/or meiosis. The alleles of the genes containing these epigenetic marks are termed epialleles. Epigenetics has been linked to cancer since 1983 by the work of Andy Feinberg and Bert Vogelstein (1-2), but has largely remained in the shadows. These changes in chromatin are now at the forefront of research in the field of oncogenesis, both as mechanisms of oncogenesis and as prognostic indicators of cancer risk. Leukemia, due to the defects in cellular differentiation associated with the disease, has important connections to epigenetic gene regulation. Cellular differentiation has been studied as a model system for epigenetic gene control in Drosophila. Homeobox genes in the antennapedia (3)  and bithorax (4, 5) gene clusters have long been known to be regulated by trithorax group and Polycomb group of genes, which regulate transcription through chromatin remodeling mechanisms. The ectopic expression of the mammalian homologs of the homeobox genes has been linked to leukemic transformation since 1988 (6), and has continued to show extensive connections (7-14). These connections that leukemia has with cellular differentiation make this group of diseases amenable to exploring the mechanisms of epigenetic gene regulation as they pertain to oncogenesis. This review will examine leukemia, with an emphasis on myelogenous leukemia, as a defect in cellular differentiation and examine possibilities of epigenetic gene regulation of oncogenes and tumor suppressor genes.