Hematopoietic stem cells (HSCs) serve as the backbone of the hematopoietic system, undergoing self-renewal and differentiation to generate the cells of all of the blood lineages. In several types of blood cancers, leukemia stem cells (LSCs) with analogous properties that underlie the expansion of malignant cells have been defined. We seek to answer two central questions pertaining to the epigenetic regulation of the self-renewal process within these cell types. One, are the epigenetic mechanisms responsible for regulating self-renewal common or distinct in HSCs and LSCs? Two, are epigenetic patterns within HSCs or LSCs programmed in response to cues from the bone marrow microenvironment? By identifying key differences in the epigenetic mechanisms underlying the regulation of HSCs and LSCs, we seek to reveal novel strategies for directed leukemia therapy.