Cystic fibrosis, the most commonly inherited lethal pulmonary disorder in Caucasians, is caused by mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR). To identify genomic responses to the presence or absence of CFTR in pulmonary tissues in vivo, microarray analyses of lung mRNAs were performed on whole lung tissue from mice lacking (CFTR(-)) or expressing mouse CFTR (CFTR(+)). Whereas the histology of lungs from CFTR(-) and CFTR(+) mice was indistinguishable, statistically significant increases in the relative abundance of 29 and decreases in 25 RNAs were identified by RNA microarray analysis. Of RNAs whose expression was consistently altered by the absence of CFTR, functional classes of genes influencing gene transcription, inflammation, intracellular trafficking, signal transduction, and ion transport were identified. RNAs encoding the transcription factor CCAAT enhancer-binding protein (CEBP) delta and interleukin (IL) 1beta, both known to regulate CFTR expression, were induced, perhaps indicating adaptation to the lack of CFTR. RNAs mediating lung inflammation including calgranulin-S100 family members, IL-1beta and IL-4, were increased. Likewise, expression of several membrane transport proteins that interact directly with CFTR were increased, suggesting that CFTR-protein complexes initiate genomic responses. Absence of CFTR influenced the expression of genes modulating diverse pulmonary cell functions that may ameliorate or contribute to the pathogenesis of CF.