Chronic inflammation is linked to carcinogenesis in several organ systems. In the lungs, NF-κB, a central effector of inflammatory responses, is frequently activated in non-small-cell lung cancer, but its role in tumor promotion has not been studied. Several lines of evidence indicate that ethyl carbamate (urethane)-induced lung tumor formation, a prototypical mouse model of multistage lung carcinogenesis, is potentiated by inflammation. We found that mouse strains susceptible to lung tumor formation (FVB, BALB/c) exhibited early NF-κB activation and inflammation in the lungs after urethane treatment. However, a resistant strain (C57B6) failed to activate NF-κB or induce lung inflammation. In FVB mice, we identified urethane-induced NF-κB activation in airway epithelium, as well as type II alveolar epithelial cells and macrophages. Using an inducible transgenic mouse model (FVB strain) to express a dominant inhibitor of NF-κB specifically in airway epithelial cells, we found that urethane-induced lung inflammation was blocked and tumor formation was reduced by >50%. Selective NF-κB inhibition resulted in increased apoptosis of airway epithelial cells at 2 weeks after urethane treatment in association with a marked reduction of Bcl-2 expression. These studies indicate that NF-κB signaling in airway epithelium is integral to tumorigenesis in the urethane model and identify the NF-κB pathway as a potential target for chemoprevention of lung cancer.