Molecular focusing on of cancer stem cells (CSCs) has therapeutic possible for effective treatment of cancer, whilst comparatively handful of specific targets are already recognized thus far. Hypoxia-inducible issue (HIF) was lately shown Estrogen Receptor to regulate the tumorigenic capacity of glioma stem cells below hypoxic disorders. Surprisingly, we discovered that, underneath normoxia, HIF1 alpha signaling was selectively activated in the stem cells of mouse lymphoma and human acute myeloid leukemia TNF-alpha signaling pathway (AML). HIF1 alpha shRNA and HIF inhibitors abrogated the colony-forming unit (cfu) exercise of mouse lymphoma and human AML CSCs. Importantly, the HIF-inhibitor echinomycin efficiently eradicated mouse lymphoma and serially transplantable human AML in xenogeneic designs by preferential elimination of CSCs. Hif1 alpha maintains mouse lymphoma CSCs by repressing a damaging feedback loop from the Notch pathway. Taken together, our success show an important function of Hif1 alpha-Notch interaction in keeping CSCs and offer an effective strategy to target CSCs for treatment of hematological malignancies.