In response to a growing national awareness that the development and use of new diagnostic, therapeutic, and preventive interventions had been occurring at a quickening pace—one far outstripping the evidence necessary to make informed decisions about their comparative advantage—the Patient-Centered Outcomes Research Institute (PCORI) was established in 2010 as part of the Affordable Care Act legislation. PCORI is guided by the imperative to help patients, families, clinicians, and other health care stakeholders make better informed health care decisions and improve care and outcomes. To inform the next steps in its organizational strategy, PCORI enlisted the National Academy of Medicine (NAM) to leverage its deep experience in convening experts on matters of significant national importance, including its long-standing thought leadership role in the realization of a learning health system. The NAM formed a multi-stakeholder workgroup and held two virtual convenings with the objective of engaging with patients, clinicians, health system leaders, researchers, and other stakeholders from the broader health community to identify and discuss high-priority emerging issues in health, health care, and biomedical science and technology. The key messages from these meetings are outlined in the Special Publication Priorities on the Health Horizon: Informing PCORI's Strategic Plan.Given the breadth of the domains considered in the Priorities on the Health Horizon meetings—emerging technologies, social and environmental factors, optimizing value, and infrastructure—a formidable set of pressing health and health care research needs were reviewed and discussed. In addition, certain fundamental strategic priorities emerged as basic and critical to progress in the field: (1) the need to reorient research perspectives and activities to patient and family priorities and values, and in particular, those conditions that drive inequities; (2) the need to foster strategic learning partnerships across groups, organizations, and sectors; and (3) the need to build the continuous learning infrastructure to produce new insights at the pace and scale necessary for health and health care improvement.Moving forward, building the capacity to continuously improve learning and sharing throughout the system will entail stakeholders working together as seamlessly as possible. The NAM and PCORI worked together to facilitate an expansive dialogue with key stakeholders and engender trust through a focus on shared commitments to progress on improving health for all Americans in the decade ahead.