Leukemias harboring rearrangements of the MLL gene carry a poor prognosis. Over the past 6 years, it has become increasingly clear that fusions of MLL induce widespread epigenetic dysregulation that may mediate much of their transforming activity. The histone methyltransferase DOT1L, which methylates histone 3 on lysine 79 (H3K79) has received particular attention. Several MLL fusions may physically interact with DOT1L. Genome-wide H3K79 methylation profiles in MLL-rearranged leukemias are abnormal, and can serve to distinguish MLL-rearranged from other types of leukemias. Loss of H3K79 methylation affects expression of MLL-target loci and is detrimental to the leukemogenic activity of MLL-rearranged cells, suggesting that transformation in these leukemias is driven by a DOT1L dependent, aberrant epigenetic program. The ‘histone code hypothesis’ proposes that histone modifications, along with proteins that recognize, place and remove these marks, form a sophisticated regulatory network that directly control gene expression. Histone modifications may prime genes for rapid induction after signaling receptor engagement, coordinate individual genes to genetic programs that are coregulated, or organize a sequence of transcriptional events during development. MLL-rearranged leukemias have recently been proposed to rely heavily on epigenetic dysregulation during malignant transformation. In contrast to most other cancers, MLL-rearranged leukemias display a remarkable paucity of DNA sequence alterations: frequently, the only genetic abnormality uncovered by genome-wide technologies in these leukemias is the MLL-translocation. The induction of widespread epigenetic changes could explain the apparent lack of a need for cooperating mutagenesis on a DNA-sequence level. This is significant, since most MLL-rearranged