We found that (1) the gene ablation of Bmi1 led to increased apoptosis, decreased proliferation, and weakened stemness of ESCC; (2) the Bmi1+ tumor cells led to the progressive growth of epithelial clones and the Bmi1+ tumor cells were tumor-initiating cells in ESCC; and (3) the cisplatin combined with Bmi1 targeting drug could effectively inhibit tumor growth in ESCC. The gene discussed is BMI1; the disease is esophageal squamous cell carcinoma.