Before the coronavirus disease (COVID-19) pandemic, the global community had been cautiously approaching a new era in global health. Between 1990 and 2015, maternal mortality worldwide dropped by 44%.1 Since 2000, the global under-5 mortality rate declined by 44%, new HIV cases decreased by 35%, and the incidence rate of TB declined by 19%. However, even with this progress, the world had not been on track to achieve its Sustainable Development Goal targets, with inequity increasing. While the ripple effects of COVID-19 will take years, if not decades, to untangle, early data demonstrate its stark impact. As of April 2021, antenatal care visits fell by 43%, malaria diagnosis fell by 31%, and HIV testing dropped 41%. COVID-19 has also highlighted the extent to which, even in the face of progress, longstanding societal inequities remain intact. COVID-19 has given global health practitioners yet another opportunity to radically rethink how we work and engage in global health moving forward. Trends like demographics, urbanization, slower and unequal economic growth, and climate change, all pose huge challenges. Our global health goals depend on our collective efforts to problem solve, strategically take risks, and quickly iterate/adapt to spur more impactful solutions. Global health practitioners and designers alike recognize that real questions remain about the application and complementarity of design in global health. Design for Health—jointly led by the Bill & Melinda Gates Foundation and the U.S. Agency for International Development— brought together donors, designers, researchers, implementing partners, and country governments to explore these questions more fully. Members of this community came together in this special issue of Global Health: Science and Practice to build upon lessons from the use of design in global health, to distill and demystify the design methodology, and simultaneously open the conversation to perspectives and questions that can generate change and new ideas to tackle the health crises of today and those on the horizon.