This study identified gene expression profiles that provided evidence for genomic mechanisms underlying the pathophysiology of aging lung. The aging lung from C57BL/6 (B6) and DBA/2 (D2) mouse strains differ in lung physiology and morphometry. Lungs were harvested from B6 mice at 2, 18, and 26 months (mos) and from D2 mice at 2 and 18 mos of age. Purified RNA was put to oligonucleotide microarray analyses, and differential expression analyses were performed for comparison of various datasets. A significant majority of differentially expressed genes were up-regulated with aging in both strains. Aging D2 lungs uniquely exhibited up-regulation in stress response genes including xenobiotic detoxification cascades. In contrast, aging B6 lungs showed down-regulation of heat shock response genes. Age-dependent down-regulation of genes common to both B6 and D2 strains included several collagen genes (e.g. Col1a1 and Col3a1). There was a greater elastin (Eln) gene expression in D2 mice at 2 mos, and Eln was uniquely down-regulated with age in this strain. The matrix metalloproteinase 14 Mmp14 gene, critical to alveolar structural integrity, was also down-regulated with aging in only D2 mice. Several polymorphisms in the regulatory and untranslated regions of the Mmp14 gene were identified between strains, suggesting that variation in Mmp14 gene regulation contributes to accelerated aging of lungs in D2 mice. In summary, lungs of B6 and D2 mice age with variable rates at the gene expression level, and these quantifiable genomic differences provide a template to understand the variability in age-dependent changes in lung structure and function.