Fusidic acid (FA) is an antibiotic used to treat staphylococcal infections, particularly Staphylococcus aureus. It acts by inhibiting protein synthesis through locking elongation factor G (EF-G) to the ribosome. In S. aureus, there are three mechanisms of resistance. Mutations in the antibiotic target, EF-G (fusA), are common. These mutations affect the FA binding or the stability of the FA-locked state of EF-G but, due to effects on the normal function of EF-G, impose a fitness cost for the pathogen. The most common mechanism, FusB-type, involves expression of a resistance protein, FusB or FusC (FusD or FusF in other staphylococci), that provides target protection. The resistance protein binds to EF-G in its FA-locked state and mediates its release from the ribosome. An uncommon resistance mechanism (FusE) involves mutations in a ribosomal protein, uL6. In other bacteria, outside of its current clinical use, resistance to FA involves efflux pumps, limited membrane permeability, or enzymes that chemically alter FA. On a global level, the prevalence of FA resistance is relatively low, indicating that the antibiotic remains effective.