Skin and soft tissue infections (SSTIs) are common, and complicated SSTIs (cSSTIs) are the more extreme end of this clinical spectrum, encompassing a range of clinical presentations such as deep-seated infection, a requirement for surgical intervention, the presence of systemic signs of sepsis, the presence of complicating co-morbidities, accompanying neutropenia, accompanying ischaemia, tissue necrosis, burns and bites. Staphylococcus aureus is the commonest cause of SSTI across all continents, although its epidemiology in terms of causative strains and antibiotic susceptibility can no longer be predicted with accuracy. The epidemiology of community-acquired and healthcare-acquired strains is constantly shifting and this presents challenges in the choice of empirical antibiotic therapy. Toxin production, particularly with Panton-Valentine leucocidin, may complicate the presentation still further. Polymicrobial infection with Gram-positive and Gram-negative organisms and anaerobes may occur in infections approximating the rectum or genital tract and in diabetic foot infections and burns. Successful management of cSSTI involves prompt recognition, timely surgical debridement or drainage, resuscitation if required and appropriate antibiotic therapy. The mainstays of treatment are the penicillins, cephalosporins, clindamycin and co-trimoxazole. β-Lactam/β-lactamase inhibitor combinations are indicated for polymicrobial infection. A range of new agents for the treatment of methicillin-resistant S. aureus infections have compared favourably with the glycopeptides and some have distinct pharmacokinetic advantages. These include linezolid, daptomycin and tigecycline. The latter and fluoroquinolones with enhanced anti-Gram-positive activity such as moxifloxacin are better suited for polymicrobial infection.