Thirty-five years ago Gross instilled papain into experimental animals resulting in emphysema (1). This finding, combined with the clinical observation by Laurell and Erickson that patients with deficiency of-1-antitrypsin (-1AT) were at increased risk of emphysema (23), formed the scientific basis for the elastase: antielastase hypothesis for the pathogenesis of emphysema. Today, this remains the prevailing theory for the development of emphysema, and animal models of chronic obstructive pulmonary disease (COPD) remain a critical experimental tool. In this issue, Suga and colleagues report that the absence of klotho results in air-space enlargement in mice (2). A more comprehensive statement of the elastase: antielastase hypothesis is that cigarette smoking causes inflammatory-cell recruitment into the lung, activating and releasing proteinases in excess of inhibitors in interstitial microenvironments. This, coupled with abnormal alveolar and matrix repair, results in emphysema. We are beginning to define the contribution of specific cells and proteinases, but we have yet to understand many crucial issues such as sites and mechanisms of airflow obstruction, as well as the molecular basis for abnormal repair. Why only a minority of cigarette smokers present with clinically significant emphysema remains a fascinating enigma, the study of which could lead to insight into mechanisms and cure.