No effective chemopreventive agents for lung cancer exist. Prostacyclin overexpression or administration of the stable prostacyclin analog, iloprost, is highly effective in preventing adenoma formation in multiple murine models of chemical carcinogenesis, including a tobacco smoke–induced tumor model. Oral iloprost is effective in improving premalignant dysplasia in former smokers in a Phase II trial, but the drug is not currently available. Basic studies have supported a PPARγ-mediated mechanism for iloprost's chemopreventive activity. Pioglitazone is a thiazolidinedione PPARγ activator and has been shown to be chemopreventive in multiple preclinical models. Keith and colleagues carried out a placebocontrolled Phase II trial (beginning on page 721) of oral pioglitazone in high-risk current or former smokers with sputum cytologic atypia or known endobronchial dysplasia. Although pioglitazone did not show efficacy in improving premalignant dysplasia in either current or former smokers, specific lesions showed histologic improvement. The results suggest that chemopreventive activity of iloprost is not purely mediated through PPARγ. Further study will be needed to better characterize responsive dysplasia. The cover image depicts the structure of pioglitazone, the drug tested in this study.