Staphylococcus aureus is the most common cause of complicated skin and soft tissue infections (cSSTIs). Antibiotic choices for these infections continue to evolve. History has seen penicillin progress to antistaphylococcal penicillins and cephalosporins, but these drugs are now giving way to drugs that are effective against methicillin-resistant S. aureus (MRSA). While vancomycin has been the gold standard to treat MRSA infections, newer therapeutic options have been developed over the last 5 years. These include quinupristin–dalfopristin, daptomycin, tigecycline and linezolid, which is the focus for this review. Linezolid is efficacious in the treatment of cSSTIs (including diabetic foot infections) caused by Gram-positive organisms (including MRSA), with a well-defined safety profile and straightforward dosing. It is also approved for nosocomial pneumonia, community-acquired pneumonia and uncomplicated skin and skin structure infections. Linezolid has an oral and parenteral formulation, which are equivalent. The oral formulation has the potential to offer economic benefits as compared with other therapies. Currently, there are only a few new antibiotics in development with MRSA activity. The proper use of all antibiotics, including these newer agents, is increasingly important if we are to slow the evolution of microbial resistance.