Thirty years ago the concept of the elastase:antielastase hypothesis was introduced. Neutrophil elastase:A1PI balance was found to be critical, predisposing patients deficient in A1PI to panacinar emphysema; however, the causative elastases in common cigarette-induced pulmonary emphysema are unclear. Several members of the serine, cysteine, and metalloproteinase families have been identified in inflammatory and resident lung cells. We propose to use gene-targeted mice, deficient in individual elastases to determine the relative contribution of candidate elastases to cigarette-smoking-related emphysema. This does not guarantee that humans will respond to cigarette smoke with the same array of elastases as mice. However, these studies may guide labor intensive therapeutic trials with specific proteinase inhibitors and ultimately lead to rational therapy.