The pressing need to measure and improve antibiotic use was recognized >40 years ago, so why have we failed to achieve sustained improvement at scale? In his 2014 Reith Lectures about the future of medicine, the US surgeon Atul Gawande said that failure in medicine is largely due to ineptitude (failure to use existing knowledge) rather than ignorance (lack of knowledge). Consequently, it is notable that most interventions to improve antimicrobial prescribing are either designed to educate individual practitioners or patients about policies or to restrict prescribing to make practitioners follow policies. Interventions that enable practitioners to apply existing knowledge through decision support, feedback and action planning are relatively uncommon. There is an urgent need to improve the design and reporting of interventions to change behaviour. However, achieving sustained improvement at scale will also require a more profound understanding of the role of context. What makes contexts receptive to change and which elements of context, under what circumstances, are important for human performance? Answering these questions will require interdisciplinary work with social scientists to integrate complementary approaches from human factors and ergonomics, improvement science and educational research. We need to rethink professional education to embrace complexity and enable teams to learn in practice. Workplace-based learning of improvement science will enable students and early-career professionals to become change agents and transform training from a burden on clinical teams into a driver for improvement. This will make better use of existing resources, which is the key to sustainability at scale.