Cystic fibrosis (CF), a common lethal pulmonary disorder in Caucasians, is caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator gene (CFTR) that disturbs fluid homeostasis and host defense in target organs. The effects of CFTR and 508-CFTR were assessed in transgenic mice that (1) lack CFTR expression (Cftr^-/-); (2) express the human 508 CFTR (CFTR⁵⁰⁸); (3) over-express the normal human CFTR (CFTR^tg) in respiratory epithelial cells. Genes were selected from Affymetrix Murine GeneChips analysis and subjected to functional classification, k-means clustering, promoter cis-elements/modules searching, literature mining and pathway exploring. Genomic responses to Cftr^-/- were not corrected by expression of CFTR⁵⁰⁸. Genes regulating host defense, inflammation, fluid and electrolyte transport were similarly altered in Cftr^-/- and CFTR⁵⁰⁸ mice. CFTR⁵⁰⁸ induced a primary disturbance in expression of genes regulating redox and antioxidant systems. Genomic responses to CFTR^tg were modest and were not associated with lung pathology. CFTR^tg and CFTR⁵⁰⁸ induced genes encoding heat shock proteins and other chaperones but did not activate the endoplasmic reticulum associated degradation pathway (ERAD). RNAs encoding proteins that directly interact with CFTR were identified in each of the CFTR mouse models, supporting the hypothesis that CFTR functions within a multi-protein complex whose members interact at the level of protein–protein interactions and gene expression. Promoters of genes influenced by CFTR shared common regulatory elements, suggesting that their co-expression may be mediated by shared regulatory mechanisms. Genes and pathways involved in the response to CFTR may be of interest as modifiers of CF.