Global health systems are challenged by escalating costs and growing demands for care created by the demands of aging populations and rising rates of chronic illness which place unsustainable pressure on health systems to meet population health needs. To overcome these challenges, transformational change is needed to strengthen health system performance and sustainability. Innovation is widely viewed as the strategy to drive transformational change in health systems; yet to date, innovation has lacked a clearly defined focus or agenda to achieve transformation. An actionable innovation agenda is needed to achieve transformational change for health systems. The key conditions for success as an innovation strategy are examined, including clearly defined innovation objectives, key milestones, and actionable steps every system stakeholder must pursue in order to guide the innovation agenda and ultimately accelerate the transformational changes needed for a sustainable healthcare system that delivers value to populations.