Centrilobular emphysema is the most common form of pulmonary emphysema, occurring primarily in smokers, and showing a predilection for the upper lobes of the lung. Panlobular emphysema is associated with, among other things, deficiency of the serum protease inhibitor, alpha 1 -antitrypsin, and in the latter situation there is a striking predilection for the bases of the lungs. A single hypothesis has been developed to explain the differing localization of these two distinct forms of emphysema, utilizing the currently accepted “proteolysis-antiproteolysis” model for the development of emphysema and also our knowledge of the distribution of ventilation, perfusion, and of the ventilation:perfusion ratios within the upright lung. Inhaled irritants such as cigarette smoke are thought to predispose to emphysema by causing the release of proteolytic enzymes from lung leukocytes and also in part by inactivating alpha 1 -antitrypsin by an oxidant effect Alpha 1 -antitrypsin is thought to play a protective role by inactivating free proteases and possibly by reducing inflammatory responses. It is hypothesized that inhaled irritants will be distributed in the lung in a manner similar to pulmonary ventilation and that alpha 1 -antitrypsin will be distributed in the lung in the same manner as pulmonary perfusion. In the smoker with normal serum alpha 1 -antitrypsin, one would thus expect the emphysema to be predominant in areas with a high smoke:alpha 1 -antitrypein ratio, which will correspond with areas with a high ventilation:perfusion ratio. In the upright human lung, the highest ventilation-perfusion ratios occur in the upper lobes of the lung, the site of predominance of centrilobular emphysema, the most common form of smoking-related emphysema. In the smoker with no alpha 1 -antitrypsin, one would expect the emphysema to occur in the areas of highest ventilation. In the upright lung, although ventilation: perfusion ratios are higher at the lung apex, ventilation considered alone is greater at the base of the lung. This provides an explanation for the predilection of alpha 1 -antitrypsin deficiency-related emphysema for the bases. Modifications of such an hypothesis may eventually explain localization of other pulmonary disorders, such as pulmonary fibroses of diverse etiologies, within the lung.