All pathogens must be able to overcome innate immunity to colonise the host and cause disease. Many do so by surviving within macrophages, long-lived innate immune cells that reside in all tissues of the body. Macrophages employ a suite of immediate, phagocytosis-coupled antimicrobial responses (e.g. phagocyte oxidase-mediated production of reactive oxygen species, lysosomal hydrolases), as well as toll-like receptor (TLR)-inducible antimicrobial pathways (e.g. inducible nitric oxide synthase-mediated production of nitric oxide, autophagy), to defend against infection. Such pathways are subverted by many medically important bacterial pathogens, for example Mycobacterium tuberculosis, Salmonella enterica and uropathogenic Escherichia coli. This talk will focus on novel TLR-inducible antimicrobial responses used by macrophages, for example metal ion poisoning, mitochondrial fission and lipid droplet-mediated host defence. It will also describe some of our efforts to manipulate these pathways as an anti-infective approach, thus highlighting the potential for host-directed therapies as a strategy to combat antibiotic-resistant bacterial infections.