Background: Assessment of deterioration of lung function in animal models of respiratory disease traditionally relies upon quantitating biochemical markers. Plethysmography is a technique for measuring lung function that includes invasive and non-invasive methodologies. Objectives: This study used whole-body barometric plethysmography to characterize change(s) in respiratory physiology of C57BL/6 mice following bleomycin administration. Methods: Cohorts of animals were culled at 3, 7, 14 and 28 days to semi-quantitatively score the lung for fibrosis, and quantitate levels of hydroxyproline in the lung. We have described in detail the response of C57BL/6 mice to bleomycin. Results: Bleomycin-treated mice had reduced minute volume (p <0.05) and an increased total breathing cycle time (p <0.0001), which consisted of a shortened inspiration time (p <0.01) and an extended expiration time (p <0.0001). Conclusions: We have demonstrated that plethysmography can be a primary indicator of the development of respiratory disease in the mouse and would thus be suitable in assessing potential therapies since any truly effective treatment should elicit restoration of respiratory parameters in addition to improving traditional biochemical and histological indices of lung function.