There is a widely acknowledged time lag in health care between an invention or innovation and its widespread use across a health system. Much is known about the factors that can aid the uptake of innovations within discrete organizations. Less is known about what needs to be done to enable innovations to transform large systems of health care. This article describes the results of in-depth case studies aimed at assessing the role of key agents and agencies that facilitate the rapid adoption of innovations. The case studies—from Argentina, England, Nepal, Singapore, Sweden, the United States, and Zambia—represent widely varying health systems and economies. The implications of the findings for policy makers are discussed in terms of key factors within a phased approach for creating a climate for change, engaging and enabling the whole organization, and implementing and sustaining change. Purposeful and directed change management is needed to drive system transformation.