Until now, most studies evaluating the efficacy of novel therapies has continued to center on the effect of the agent tested on FEV1. This approach is justified when only evaluating the bronchodilator property of a medication, as has been true for asthma, but fails to consider much more promising mechanistic therapies that can have effects beyond bronchodilation. Indeed, as we unravel the injury and repair mechanisms involved in the pathogenesis of COPD, we must expand the ways in which to evaluate therapies that may modify those mechanisms. Inflammation plays an important role in the perpetuation of COPD. Recent evidence2 has indicated that in patients who have stopped smoking long before portions of the lung were removed for therapeutic pneumoplasty, there is an active inflammatory process with evidence of abnormal repair. This issue of CHEST (page 56) includes a report by Rennard and coworkers,9 of a relatively short-term (6 months) trial testing the efficacy of a novel antiinflammatory agent, cilomilast. This agent is one of the members of the family of phosphodiesterase (PDE) 4 inhibitors, which in vitro have been shown to suppress the production of cytokines, cell proliferation, and chemotaxis, the release of inflammatory mediators, and nicotinamide adenine dinucleotide phosphate oxidase activity.,3PDE4 inhibitors also have activity in animal models of airway inflammation.4Through its action on cyclic adenosine monophosphate and guanosine monophosphate, PDE4 inhibitors have effects on various inflammatory cells including epithelial cells, dendritic cells, eosinophils, macrophages, mast cells, monocytes, basophils, and T and B lymphocytes. Administered orally, the agents reach the lungs via the systemic circulation, a fact that provides direct access to the most distal portions of the lungs, the site of the small airways. This is important since most inhaled bronchodilators or inhaled corticosteroids may not fully reach the distal portion of the airways where a large share of the inflammatory process seems to continue unabated. Based on the current knowledge of inflammation and the natural course of COPD, a 6-month window to evaluate the effect of a therapy is very short and can only provide “proof of concept” rather than “definitive” data regarding the value of the intervention. It is very encouraging that the data provided by Rennard and coworkers showed an FEV1 difference in favor of cilomilast compared to placebo. Even more interesting is the larger difference in the quality-of-life score measured with the St. George questionnaire, which reached the minimal important difference of 4 U after only 6 months of therapy. These findings are in line with those recently reported5 for roflumilast in a similar large 6-month trial. In addition, even though it was only a secondary outcome of the two studies, patients in both studies receiving the PDE4 inhibitors had a delay in the time to the next exacerbation. The 40-mL difference in FEV1 between cilomilast and placebo is unlikely to explain the difference in health status and the recurrence of exacerbation between groups.