MLL fusion oncogenes are pathogenically associated with 5-10% of human acute leukemias. Through multiple interactions with chromatin regulatory factors, they convert a normal hematopoietic hierarchy into a leukemia cell hierarchy sustained at its apex by a population of inappropriately self-renewing myeloid cells termed leukemia stem cells (LSCs). Initiation of the aberrant leukemia cell hierarchy is associated with an abnormal epigenetic state at Hoxa and Meis1 loci, with concomitant high level Hoxa and Meis1 expression. This introduces at the level of the myeloblast, or thereabouts, a finite probability of self-renewal division where none previously existed. In contrast, differentiation-mediated exit of LSCs from the self-renewing compartment of the leukemia clone depends on the prevailing levels of the transcription factor Myb, which functions as part of an LSC maintenance program influenced, but not directly controlled, by Hoxa and Meis1. Critical biologic and molecular differences between self-renewing progenitor-like LSCs and hematopoietic stem cells could potentially be targeted by novel therapeutic strategies.