Thoracic cavity radiotherapy is limited by the development of alveolitis and fibrosis in susceptible patients. To define the response to 18 Gy pulmonary irradiation in mice at the gene expression level and to identify pathways that may influence the alveolitis and fibrosis phenotypes, expression profiling was undertaken. Male mice of three strains, A/J (late alveolitis response), C3H/HeJ (C3H, early alveolitis response) and C57BL/6J (B6, fibrosis response), were exposed to thoracic radiation and euthanized when moribund, and lung tissue gene expression was assessed with microarrays. The responses of A/J and C3H mice were more similar to each other (60% of differentially expressed genes detected in both strains) than to that of B6 mice (17% overlap). Pathway analysis revealed the expression of complement and of B-cell proliferation and activation genes to distinguish fibrosis from the alveolitis response and cytokine interactions and intracellular signaling differed between A/J and C3H mice. A genomic approach was used to identify specific pathways that likely contribute to the lung response to radiation as fibrosis or alveolitis in mice.