Active bacterial metabolism is a prerequisite for optimal activity of many classes of antibiotics. Hence, bacteria have developed strategies to reduce or modulate metabolic pathways to become tolerant. This review describes the tight relationship between metabolism and tolerance in bacterial biofilms, and how physicochemical properties of the microenvironment at the host–pathogen interface (such as oxygen and nutritional content) are key to this relationship. Understanding how metabolic adaptations lead to tolerance brings us to novel approaches to tackle antibiotic-tolerant biofilms. We describe the use of hyperbaric oxygen therapy, metabolism-stimulating metabolites, and alternative strategies to redirect bacterial metabolism towards an antibiotic-susceptible phenotype.