The growing burden of chronic disease, an aging population, and rising health care costs threaten the sustainability of our current model for health care delivery. At the same time, innovations in predictive health offer a pathway to reduce disease burden by preventing and mitigating the development of disease. Academic health centers are uniquely positioned to evaluate the comparative effectiveness of predictive and personalized health interventions, given institutional core competencies in innovative knowledge development. The authors describe Emory University's commitment to integrating comparative effectiveness research (CER) into predictive health programs through the creation and concurrent evaluation of its Center for Health Discovery and Well Being (hereafter, “the Center”). Established in 2008, the Center is a clinical laboratory for testing the validity and utility of a health-focused rather than disease-focused care setting. The Center provides preventive health services based on the current evidence base, evaluates the effectiveness of its care delivery model, involves trainees in both the delivery and evaluation of its services, and collects structured physical, social, and emotional health data on all participants over time. Concurrent evaluation allows the prospective exploration of the complex interactions among health determinants as well as the comparative effectiveness of novel biomarkers in predicting health. Central to the Center is a cohort study of randomly selected university employees. The authors describe how the Center has fostered a foundation for CER through the structured recruitment of study cohorts, standardized interventions, and scheduled data collection strategies that support pilot studies by faculty and trainees.