Lung volume reduction surgery (LVRS) is one of a long lineage of surgical approaches to emphysema. The reintroduction of this operation in the mid-1990s led to great controversy over the value of the procedure and its long-term outcomes. The National Emphysema Treatment Trial (NETT) represented an historical scientific collaboration of the National Institutes of Health (NIH), the Centers for Medicare and Medicaid Services (CMS), and the Agency for Health Research and Quality (AHRQ). NETT was designed primarily as a pivotal surgical clinical trial, but also incorporated data collection to inform health policy and cost-benefit analyses. NETT faced challenges that included practical and ethical matters, statistical design and analysis issues, and intense public and political scrutiny. The study design required the development of methods for pulmonary rehabilitation, lung imaging, and exercise testing that have become templates for current clinical and research practice. During the course of the trial, the confidential deliberations of the Data and Safety Monitoring Board (DSMB) played an important role in the ultimate success of the trial and protection of research participants. Because of the importance of the NETT outcomes, the results were disseminated to the medical community and transformed into health policy in a rapid and efficient manner. In many ways, the story of NETT serves as a model for evaluation of new surgical approaches to chronic diseases.