Use of randomized clinical trials (RCTs) to inform clinical and policy decisions—even when trials are impeccably designed and conducted—requires the application of trial results to patients who differ from trial participants in significant ways. We propose to develop and evaluate methods for assessing the applicability of RCT results and transporting trial results to broader target populations. A seven-member stakeholder panel of patients, clinicians, methodologists, guideline developers, and representatives of federal agencies will participate in the design and conduct of this project. Our methods will allow decision makers to: 1) formally assess the applicability of trials to target populations, and 2) “transport” trial results to patient populations and (subgroups of patient populations) seen in clinical practice. Our approach combines causal inference theory, computer simulation studies, and empirical analyses of trial and observational data on high-impact clinical areas. We will apply insights from theoretical and simulation studies to two high-impact clinical topics: 1) thrombolysis treatment for acute ischemic stroke, and 2) revascularization and medical therapy for chronic coronary artery disease.