Evidence-based medicine (EBM) is central to efforts to improve the quality, safety, and affordability of health care. Randomized controlled trials (RCTs) are generally considered the highest level of evidence for assessing the effectiveness of interventions, and they serve as a foundation for EBM practice standards and performance measurements. However, critics cite the limited usefulness of applying EBM to individual patients, partly because RCTs often fail to enroll subjects who are representative of patients seen in the community. This failure yields inequity in the provision of high-quality care and creates potential for patient harm. Trialists have come a long way since the landmark 1985 Physicians’ Health Study of low-dose aspirin for the primary prevention of cardiovascular disease enrolled > 90% white male subjects; disparate enrollment still occurs, however, for important and prevalent patient subgroups.