Lung cancer is the most common cause of cancer deaths. The expression of the transcription factor C/EBPa (CCAAT/enhancer binding protein a) is frequently lost in non-small cell lung cancer, but the mechanisms by which C/EBPa suppresses tumor formation are not fully understood. In addition, no pharmacological therapy is available to specifically target C/EBPa expression. We discovered a subset of pulmonary adenocarcinoma patients in whom negative/low C/EBPa expression and positive expression of the oncogenic protein BMI1 (B lymphoma Mo-MLV insertion region 1 homolog) have prognostic value. We also generated a lung-specific mouse model of C/EBPa deletion that develops lung adenocarcinomas, which are prevented by Bmi1 haploinsufficiency. BMI1 activity is required for both tumor initiation and maintenance in the C/EBPa-null background, and pharmacological inhibition of BMI1 exhibits antitumor effects in both murine and human adenocarcinoma lines. Overall, we show that C/EBPa is a tumor suppressor in lung cancer and that BMI1 is required for the oncogenic process downstream of C/EBPa loss. Therefore, anti-BMI1 pharmacological inhibition may offer a therapeutic benefit for lung cancer patients with low expression of C/EBPa and high BMI1.