Leukemias depend on transformed stem cells for their growth and thus these cells represent important therapeutic targets. However, leukemic stem cells resemble normal hematopoietic stem cells (HSCs) with respect to most surface markers, gene expression patterns, and ability to be transplanted. Furthermore, the microenvironment that supports healthy HSCs non-hematopoietic populations, and immune cells correspondingly, the cytokines, adhesion molecules and signal transduction pathways are also impaired during leukemogenesis. This altered environment promotes leukemic growth specifically through pro-inflammatory cytokines. Here, we characterize normal and leukemic signaling, as well as the instructive cues from the neighboring hematopoietic cells and the microenvironment that promote stem cell self-renewal and differentiation.