The “cancer stem cell” hypothesis has emerged as the leading paradigm in how we view the origin and perpetuation of neoplastic-initiating cells in leukemia and solid tumors (for review, see Buzzeo et al. 2007). Central to this model is the concept that only a rare subpopulation of cells in the malignant clone retains or acquires the ability to self-renew and proliferate to initiate and maintain the disease. Although hematopoietic stem cells (HSC) with inherent self-renewal properties are generally believed to be the initiating cells for malignant transformation in acute leukemias, it is now evident that the target stem cell of origin for select oncogenic mutations includes committed hematopoietic progenitors. While substantial evidence supports a leukemic stem cell (LSC) model in both acute myeloid and chronic leukemias, details of the molecular processes regulating LSC properties remain poorly resolved. Insights into these processes have recently emerged from recognition that many key regulators of HSCs and LSCs are transcription factors, as evidenced by their obligatory expression in normal primitive hematopoietic cells and/or their involvement in leukemia-specific translocations. Chromosomal translocations involving the Mixed Lineage Leukemia (MLL) gene (11q23) fuse N-terminal sequences of MLL to one of> 40 functionally diverse group of C-terminal fusion partners (Daser and Rabbitts 2005) and constitute 5% of all acute myeloid leukemia (AML) cases and 22% of those with acute lymphoblastic leukemia (ALL)(De Braekeleer et al. 2005). Leukemias associated with MLL rearrangements generally have a poor prognosis and are associated with poor response to chemotherapy (Eguchi et al. 2005). Gene expression analyses of all types of MLL fusion-associated leukemias revealed HOX gene dysregulation (Rozovskaia et al. 2001; Armstrong et al. 2002; Yeoh et al. 2002; Ferrando et al. 2003), implicating HOX genes as integral factors in MLL fusion-associated leukemias. This is not surprising, as both wild-type MLL and MLL oncogenic fusions directly bind to regulatory regions within Hox gene clusters and maintain the active transcription state of these genes (Yu et al. 1995, 1998; Milne et al. 2005; Caslini et al. 2007). Furthermore, coactivation of HOXA9 with the HOX cofactor MEIS1 is a frequent occurrence in leukemias associated with MLL rearrangements (Yeoh et al. 2002; Kohlmann et al. 2003; Tsutsumi et al. 2003; Fine et al. 2004), and may represent a common molecular pathway that unifies the oncogenic potential of these diverse MLL fusion genes. Indeed, Meis1 is also a transcriptional target of select MLL oncoproteins (Milne et al. 2005) and co-overexpression of HoxA9 and Meis1 in murine bone marrow (BM) can recapitulate MLL-ENL-induced immortalization of myeloid progenitor cells (Zeisig et al. 2004).