Chronic obstructive pulmonary disease (COPD) affects 200 million people worldwide, and is projected by the World Health Organization to be the third leading cause of death world-wide by 2030. Few drugs are available to treat COPD, and none that lead to improvements in long-term survival. A major problem for drug discovery is a poor understanding of COPD pathogenesis. Animal models of COPD rely on demonstration of emphysema and airway wall thickening on histology, which generally require 6 months of daily cigarette smoke exposure. Functional changes however may develop sooner as the disease process begins in small airways. To identify changes in lung micro-structure and function during daily cigarette smoke exposures (1 or 3 months), we used respiratory-gated micro-computed tomography (micro-CT) and image-based measurements of lung and airway volume and gas content. Mice were imaged pre-exposure, exposed daily to tobacco cigarette smoke, and imaged again. Images representing peak inspiration and end expiration were reconstructed with 0.075 mm isotropic voxel spacing. Significant differences were observed between pre-exposure and post-exposure scans for the lung volume, and air content at peak inspiration and for tidal volume in the control mice. These results suggest that the lung capacity of the mice continued to develop over the exposure period in control mice. The 3-month smoke-exposed mice exhibited increased lung volumes compared to 1-month and control groups for both respiratory phases. <i>In vivo</i> respiratory-gated micro-CT imaging is an effective non-invasive means of monitoring the progression of respiratory disease as early as 1 month into a smoke-exposure study.