Cystic fibrosis (CF) is a common and fatal recessive disease, which is caused by dysfunction of a chloride ion channel, termed the CF transmembrane conductance regulator (CFTR). The CF gene was cloned in 1989; subsequently, several mouse models have been created using gene targeting within embryonic stem cells. This report describes how such animal models provide the opportunity to elucidate disease pathogenesis, correlate genotype with phenotype and develop novel therapies. The current models encompass mice with a complete knockout of CFTR function, with residual CFTR function, and with precise mutations corresponding to those in humans that precipitate CF. All the CF mice demonstrate the characteristic CF ion-transport defect and show some evidence of intestinal disease, but they have a variable level of survival. Genetic background has also been shown to affect the intestinal phenotype of CF mice and this has allowed identification of a genetic modifier locus of CF in humans. Lung disease in human CF is the major cause of death in early adulthood. This is not entirely reproduced in CF mice, but repeat exposure of the lung to clinical pathogens does reveal a significantly abnormal pathogen-related response in the residual-function mice. CF mice have been successfully used to investigate the safety and efficacy of various pharmacological and gene-therapy protocols. As new cloning techniques become available, the models can be refined to ensure that in vivo models continue to be an essential tool for studying CF.