Comparative effectiveness research is a tool to use in achieving patient-centered, high-value health care. However, applying the results to individual patients and health systems raises unique issues. Here, we review lessons learned by the Veterans Health Administration (VHA) in developing and implementing the research in a large integrated health system. Decision makers should examine whether individual studies apply to diverse populations, align tools and incentives to adopt evidence-based practices, and consider both the patient and population perspectives. A key challenge remains how to incorporate comparative evidence and patient values into busy clinical practices.