Serine proteinases have diverged evolutionarily from a single gene product undergoing duplication and mutations yielding enzymes with diverse biologic functions, including digestive enzymes of exocrine glands, clotting factors, and leukocyte granule–associated proteinase such as neutrophil elastase. Neutrophil elastase (NE) is a 30-kD glycoprotein chymotrypsin-like serine proteinase with potent catalytic activity dictated by a catalytic triad that consists of His, Asp, and Ser residues that form a charge relay system (1). NE, along with cathepsin G (CG), and proteinase 3 (PR3), are formed in a lineage-restricted and developmentally specific manner during the development of myeloid cells, and stored in granules as active packaged proteins. Despite extensive knowledge of NE, the enzyme, we still struggle to understand its biologic function (s). Whereas the role of other serine proteinases as digestive enzymes and clotting factors is clear, most of our knowledge regarding NE revolves around its capacity to cause tissue destruction. Indeed, NE appears to cause more trouble than it is worth. This has been the basis for development of inhibitors, including the novel and potent EPI-HNE-4, described by Delacourt and coworkers in this issue (2). NE has been estimated to be present at high concentrations (5 mM) in neutrophil azurophil granules. It is hard to believe that this destructive enzyme would be tolerated in such large amounts if it did not serve important biologic functions. Moreover, the fact that α1-antitrypsin (α1-AT) is one of the most abundant extracellular proteins, and a prominent part of the acute phase response, suggests that NE is not meant to roam the extracellular space. When optimally primed by biologically relevant agonists, neutrophils release less than 2% of their total NE into the extracellular space, but they are able to translocate by “quantum bursts” of granules as much as 12% of their total NE to the cell membrane where the enzyme is active and resistant to inhibition (3). NE could be released from the cell during “frustrated phagocytosis” and following cell death if not taken up by macrophages. It is under these circumstances that NE is probably most destructive.