Cancer stem cells (CSCs) are thought to initate and perpetuate several malignancies including acute myelogenous leukemia (AML) and breast cancer. Recent evidence has shown that cancer stem cells (CSCs) represent a relatively quiescent subpopulation of cells that is refractory to current therapeutic treatments. Thus, it has been suggested that this population of CSCs may result in disease relapse. Therefore, CSCs represent a critical therapeutic target for improving clinical outcomes. Specifically, we have demonstrated that AML stem cells exist in a molecular state that is unique from their normal hematopoietic counterparts. Since these features are absent in normal cells, I successfully employed both molecular genetic and small molecule strategies that exploit these differences to selectively ablate AML at the bulk, stem, and progenitor level, with no appreciable toxicity to their normal hematopoietic counterparts.