Shaver discusses the study by M.C. McKelvey and colleagues on the role of cathepsin S in triggering neutrophilic inflammation during ARDS. The authors use BAL samples from patients with ARDS to show clinical relevance of elevated cathepsin S. Patients with ARDS have elevated cathepsin S levels and activity and lower levels of its inhibitor cystatin SN in bronchoalveolar lavage. Patients with both pulmonary and nonpulmonary ARDS have significant changes in cathepsin S and cystatin SN, suggesting that this pathway could be of broad importance across the ARDS population. These observations are coupled with a series of elegant mechanistic studies in mouse models of acute lung injury to show that cathepsin S augments lung inflammation in vivo. The authors demonstrate that interruption of cathepsin S pathways attenuates neutrophilic inflammation and acute lung injury in mice.