Clara cell secretory protein (CCSP) is the most abundant secreted protein within airways of the lung. Moreover, CCSP levels are modulated in human lung disease, supporting a potentially important role for CCSP and/or Clara cells in lung homeostasis. However, in vivo roles for CCSP remain elusive. A popular hypothesis is that CCSP is a regulator of the inflammatory response. The purpose of this review is to provide an overview of the phenotype of CCSP null mice and relate this phenotype to proposed functions for the protein. Phenotypic analysis of mice homozygous for the CCSP-1 null allele of the CCSP gene (CCSP-/-1) revealed susceptibility to inhaled oxidant gases. Sensitivity of CCSP-/-1 mice to inhaled ozone is unrelated to alterations in antioxidant defenses, but is associated with increased cellular injury. Additional studies investigating inflammatory control in CCSP deficient mice found no differences between wild-type and CCSP-/-1 mice in their inflammatory response to low-dose inhaled endotoxin exposure, arguing against a role for CCSP in regulation of pulmonary inflammation. The findings among CCSP-/-1 mice of ultrastructural alterations to Clara cell secretory apparatus, with associated changes in airway lining fluid protein composition, demonstrate that the CCSP-/-1 genotype results in more complex changes to airways than CCSP deficiency per se. It can be concluded that CCSP does not regulate endotoxin-induced pulmonary inflammation. Moreover, CCSP-/-1 mice represent a valuable tool for probing functional roles for Clara cells in regulation of airway lining fluid composition and lung pollutant susceptibility.