Serine proteases have been implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD) since the identification of alpha 1-antitrypsin deficiency in 1963. This inhibitor efficiently inactivates several enzymes released by activated neutrophils including neutrophil elastase, cathepsin G and proteinase 3, all of which have been shown to generate features of COPD in animal models. Recent studies have identified the mechanisms of enzyme release from activated neutrophils and indicate that the concentrations are usually two orders of magnitude above that of normal alpha 1-antitrypsin. This results in an area of obligate proteolysis in the immediate vicinity of a migrating neutrophil. The area is greatly enlarged in alpha 1-antitrypsin deficiency explaining the increased susceptibility of such patients to develop lung damage. The migration into and activation of neutrophils in the lung is likely to be a major determinant of the development of COPD. Understanding the processes has important implications for the design of new therapeutic strategies.