Health care in America is in crisis. Population health and patient outcomes are deteriorating relative to the rest of the developed world, and much of the health care delivered today is not based on rigorous scientific evidence. This is attributable, in large part, to a failing clinical research enterprise. From the perspective of patients and the general public, science rarely answers questions that “matter”; the public’s trust in medical science is eroding; and patients often lack a clear understanding of the necessary role scientific research plays in all medical innovations. From the perspective of many practicing physicians, clinical research is burdensome, time-consuming, and costly. The pressures of day-to-day practice provide little opportunity for physicians to gain complete knowledge of the current universe of clinical research in order to understand how participation might benefit their patients. From the perspective of health systems, clinical research is often seen as a costly distraction from the primary patient care mission. And while advancing science is an oft-stated goal, it is no substitute for increasing clinical volumes, especially in challenging economic times. Absent a strong business case, health system leaders have little incentive to invest in clinical research infrastructure or capacity-building. Despite these challenges, our need for scientific evidence that can be rapidly implemented into clinical practice has never been greater.