Rising levels of antimicrobial and pesticide resistance increasingly undermine human health and systems for biomass production, and emphasize the sustainability challenge of preserving organisms susceptible to these biocides. In this Review, we introduce key concepts and examine dynamics of biocide susceptibility that must be governed to address this challenge. We focus on the impact of biocides on the capacity of susceptible organisms to prevent spread of resistance, and we then review how biocide use affects a broader suite of ecosystem services. Finally, we introduce and assess the state of what we term the Anthropocene operating space of biocide susceptibility, a framework for assessing the potential of antibiotic and pesticide resistance to undermine key functions of human society. Based on current trends in antibiotic, insecticide and herbicide resistance, we conclude that the states of all six assessed variables are beyond safe zones, with three variables surpassed regionally or globally.