Fusidic acid has activity against a range of pathogens but has mainly been used to treat staphylococcal infections. Fusidic acid monotherapy, especially topical preparations, has been strongly associated with the emergence of fusidic acid resistance among both methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-susceptible S. aureus. Key resistance determinants include mutations in the fusA gene, which encodes elongation factor G, and plasmid-mediated resistance (i.e., acquisition of resistance gene fusB). Clonal outbreaks of fusidic acid-resistant S. aureus have been noted throughout the United Kingdom and Europe, such that the efficacy of fusidic acid is threatened. Fusidic acid in combination with other agents, such as rifampicin, has proven effective for difficult-to-treat MRSA infections and provides a convenient oral alternative to oxazolidinones. Ensuring that systemic fusidic acid is always used in combination and that the use of topical fusidic acid is either abolished or restricted will be vital if we are to prevent the loss of this potentially useful agent.