By focusing on HIF-1α, the impact of NOTCH1-induced stemness, which controls the reaction to chemotherapy or radiotherapy as well as the malignancy in CD44+ HNSCCs, was reduced. Targeting the signaling of HIF-1α/NOTCH1 could potentially serve as a therapeutic approach for the treatment of HNSCC. The gene discussed is NOTCH1; the disease is head and neck squamous cell carcinoma.