Clara cells are nonciliated secretory cells lining the respiratory epithelium and are easily identified by the expression of Clara cell secretory protein (CCSP). To investigate molecular mechanism(s) regulating Clara cell function in the lungs, Cre recombinase was inserted into exon 1 of the CCSP, generating two novel mouse models, CCSP^Cre‐Neo and CCSP^Cre. These two models differ only by the inclusion of the neomycin resistance gene. These mice were bred to the R26R reporter mouse to investigate the tissue and cell specificity of Cre‐mediated recombination. The efficiency of Cre recombination in the CCSP^Cre mouse model was higher than in the CCSP^Cre‐Neo mouse model. Recombination was detected at D 4.5 in CCSP^Cre‐Neo/R26R mice and at D 0.5 in CCSP^Cre/R26R mice. The CCSP^Cre‐Neo and CCSP^Cre mouse models provide valuable tools for the ablation of genes in the postnatal mouse Clara cells. genesis 46:300–307, 2008. © 2008 Wiley‐Liss, Inc.