We learned many unanticipated and valuable lessons since we started planning our study of low-dose computed tomography (CT) screening for lung cancer in 1991. The publication of the baseline results of the Early Lung Cancer Action Project (ELCAP) in Lancet 1999 showed that CT screening could identify a high proportion of early, curable lung cancers. This stimulated large national screening studies to be quickly started. The ELCAP design, which provided evidence about screening in the context of a clinical program, was able to rapidly expand to a 12-institution study in New York State (NY-ELCAP) and to many international institutions (International-ELCAP), ultimately working with 82 institutions, all using the common I-ELCAP protocol. This expansion was possible because the investigators had developed the ELCAP Management System for screening, capturing data and CT images, and providing for quality assurance. This advanced registry and its rapid accumulation of data and images allowed continual assessment and updating of the regimen of screening as advances in knowledge and new technology emerged. For example, in the initial ELCAP study, introduction of helical CT scanners had allowed imaging of the entire lungs in a single breath, but the images were obtained in 10 mm increments resulting in about 30 images per person. Today, images are obtained in submillimeter slice thickness, resulting in around 700 images per person, which are viewed on high-resolution monitors. The regimen provides the imaging acquisition parameters, imaging interpretation, definition of positive result, and the recommendations for further workup, which now include identification of emphysema and coronary artery calcifications. Continual updating is critical to maximize the benefit of screening and to minimize potential harms. Insights were gained about the natural history of lung cancers, identification and management of nodule subtypes, increased understanding of nodule imaging and pathologic features, and measurement variability inherent in CT scanners. The registry also provides the foundation for assessment of new statistical techniques, including artificial intelligence, and integration of effective genomic and blood-based biomarkers, as they are developed.