Hospital- and community-acquired Staphylococcus aureus infections pose a substantial burden in terms of morbidity, mortality and healthcare costs. The introduction of new antibiotics to counter this pathogen has frequently been closely followed by the emergence of resistant strains. Most significantly, S. aureus isolates resistant to β-lactams have become common, and many of these are also resistant to β-lactamase-resistant penicillins. The rapid spread of methicillin-resistant S. aureus (MRSA) clones across the world often results in hospital outbreaks, but implementation of appropriate control measures usually reduces prevalence to sporadic levels. However, the recent emergence of MRSA infections in the community, affecting patients with no established risk factors for MRSA acquisition, is likely to impact significantly on future strategies for control of nosocomial MRSA. In contrast to other antibiotic classes, S. aureus resistance to glycopeptides did not emerge until nearly 40 years after their clinical introduction, and as a result this drug class has remained the mainstay of treatment for MRSA infections. However, a number of vancomycin-intermediate S. aureus isolates have emerged worldwide and four fully resistant S. aureus isolates have been reported in the USA. This raises the concern that the current first-line treatment for MRSA infection may become ineffective in an increasing proportion of cases in the near future. New classes of antibiotic are urgently needed to treat infections with this growing population of multidrug-resistant S. aureus, and the recently introduced oxazolidinone linezolid and the cyclic lipopeptide daptomycin are welcome additions to the ever-narrowing range of therapies effective against this pathogen.