The NF-κB/Rel family of transcription factors induces many genes involved in immune and inflammatory responses. Mice with germline deletions of individual NF-κB/Rel subunits have different phenotypes, suggesting that the NF-κB/Rel transcription factors have different functions. We tested whether c-Rel promotes allergic asthma using a murine model of allergen-induced pulmonary inflammation and airway hyperresponsiveness. Our investigation focused on c-Rel, which is expressed in lymphoid cells and is important for lymphocyte activation. In response to allergen sensitization and challenge, c-Rel-deficient mice did not develop increases in pulmonary inflammation, bronchoalveolar lavage fluid eosinophilia, or total serum IgE. c-Rel deficiency also prevented the induction of airway hyperresponsiveness. Allergen-treated wild-type mice had increased DNA binding to an NF-κB consensus site. Chemokine expression was altered in allergen-treated c-Rel-deficient mice. Monocyte chemoattractant protein-1, which is regulated by NF-κB, was decreased in allergen-treated c-Rel-deficient mice relative to wild-type controls. The increase in NF-κB/Rel transcription factors after allergen challenge in wild-type mice and the decrease in allergen reactivity found in c-Rel-deficient mice indicate that c-Rel promotes allergic inflammation. Alteration of pulmonary chemokine expression in c-Rel-deficient mice may inhibit allergen-induced pulmonary inflammation and airway hyperresponsiveness.