Antimicrobial resistance is among the most urgent global health challenges of our time, with an estimated 4·95 million deaths associated with resistant bacteria in 2019. That microbes develop resistance to antimicrobials is accepted as an evolutionary inevitability for their survival, driven by competition between and among micro-organisms in the natural environment. How to reduce the impact of drug resistance in the future is a matter of global concern, considering the consequences that clinically ineffective antimicrobials will have for health care and agricultural systems that have come to rely on these powerful substances. Paradoxically, this reliance, underpinning massive use of antimicrobials, is understood to drive antimicrobial resistance in humans, animals, and the environment. Planning for a future with antimicrobial resistance, and reducing its burden in clinical, social, and economic terms, will require addressing this paradox.