To generate needed improvements in health care, its delivery, and its outcomes, organized and sustained efforts at continuous improvement are needed. The Institute of Medicine’s Roundtable on Value & Science-Driven Health Care has developed the vision of a health care system that gets the right care to the right people when they need it, and captures the results for making improvements: a learning health system. The Roundtable sees the creation of generalizable new knowledge as a necessary, routine aspect of the delivery of health care. Activities that involve measurement, comparison, evaluation, systematic introduction of accepted therapies, sharing of experience and information, and coordination of these activities among organizations, either are, or should become, normal expected activities of such organizations. Ambiguity around the degree to which such continuous-improvement activities, including both clinical-effectiveness assessment and quality improvement, are seen as human-subject research has been a burden to those working in the field, to their institutions, and to patients. For this critical work to be done, it is imperative that there be a clear framework for whether or not human-subject research requirements apply. We believe a risk-based framework, in which oversight is commensurate with the level of risk imposed by the study, is the right approach. This framework proposes that for studies that seek only to collect information or that carry no more than minimal risk, that human-subject investigational review board (IRB) review may not be warranted. We recommend that in addition, it is essential to determine whether these activities are 1) routine clinical-effectiveness assessments and quality-improvement activities that are appropriate activities of the health care system, or 2) whether they are sufficiently separate from routine care that they should be classified as human-subject research, as covered by the Common Rule. We believe that the former, clinical-effectiveness assessment and quality improvement involving accepted therapies, should be excluded from regulation and oversight as human-subject research, but rather should be subject to the oversight and regulations appropriate to all clinical care. Both human-subject research and continuous-improvement assessments by learning organizations are crucial social goods that should be facilitated, not impaired, in the interest of the public. Adjustments in the Common Rule that will facilitate the ethical and safe conduct of human-subject research are welcome changes. However, applying the Common Rule, even with enhancements, to continuous-improvement activities that clinicians and health systems are obligated to carry out, could in fact impair the actual optimal delivery of health care advances from such research. Health care organizations already bear responsibility for overseeing the safe and effective delivery of care, and they and society have many mechanisms to be sure this responsibility is fulfilled. It is entirely logical to define their responsibility to include identifying and then disseminating knowledge about best treatments and practices, and assign the oversight responsibility to them. Realigning responsibilities in this way will reinforce the understanding that quality, safety and effectiveness assessments, and care innovation are the core of a learning health system.