Decades of overuse, misuse, and environmental antibiotic pollution has increased the global pool of resistant bacteria. With estimates of hundreds of thousands of annual human deaths and a lack of new drugs to replace old ones, antimicrobial resistance probably constitutes one of the greatest human health and sustainability challenges of the 21st century. To safeguard treatable infections, a deliberate social-ecological transformation is needed toward stewardship of the global microbiome and long-term sustainable use of antibiotics. We review the foundation for such a transformation using recent insights from sustainability science, evolutionary biology and health, and the understanding of human interactions with microbes as two intertwined complex adaptive systems. A coherent strategy should acknowledge humans as the source of the world's strongest evolutionary force, reflect that antibiotics are building blocks of modern health systems, and strive to build social-ecological resilience to minimize levels of resistance and avoid over dependency on innovation of new drugs. Bottom up opportunities for seeding the transformation include participatory monitoring and stewardship of our personal and environmental microbiomes, as well as collective consumer action. Top down priorities include regular international institutions to coordinate multi-level action.