Multiple crises are triggering turbulence, instability and insecurity in contemporary societies, with impacts on economies, the environment, politics, and global affairs. An effective response will require governments to be more ambitious and act with greater urgency in their science, technology and innovation (STI) policies to meet global challenges. Sustained investments and greater directionality in research and innovation activities are needed, and these should coincide with a reappraisal of STI systems and STI policies to ensure they are “fit-for-purpose” to contribute to transformative change agendas. This policy paper provides a framework to support governments in making these assessments. It identifies six STI policy orientations for transformative change that should guide these assessments. It applies these orientations across multiple areas of STI policy, including R&D funding, the research and innovation workforce, and international R&D co-operation, and outlines a series of concrete policy actions STI policymakers can take to accelerate transformative change.