Human acute myelogenous leukemia (AML) is thought to arise from a rare population of malignant stem cells. Cells of this nature, herein referred to as leukemic stem cells (LSCs), have been documented for nearly all AML subtypes and appear to fulfill the criteria for stem cells in that they are self-renewing and give rise to the cells found in many leukemic populations. Because these cells are likely to be critical for the genesis and perpetuation of leukemic disease, the present studies sought to characterize unique molecular properties of the LSC population, with particular emphasis on the transcription factor, nuclear factor-κB (NF-κB). Previous experiments have shown that unstimulated human CD34⁺ progenitor cells do not express NF-κB. In contrast, primary AML CD34⁺ cells display readily detectable NF-κB activity as assessed by electrophoretic mobility shift assay and gene expression studies. Furthermore, detailed analyses of enriched AML stem cells (CD34⁺/CD38⁻/CD123⁺) indicate that NF-κB is also active in the LSC population. Given the expression of NF-κB in leukemic, but not normal primitive cells, the hypothesis that inhibition of NF-κB might induce leukemia-specific apoptosis was tested by treating primary cells with the proteasome inhibitor MG-132, a well-known inhibitor of NF-κB. Leukemic CD34⁺/CD38⁻ cells displayed a rapid induction of cell death in response to MG-132, whereas normal CD34⁺/CD38⁻ cells showed little if any effect. Taken together, these data indicate that primitive AML cells aberrantly express NF-κB and that the presence of this factor may provide unique opportunities to preferentially ablate LSCs.