Complicated skin and soft tissue infections (cSSTIs) are the more extreme end of clinical spectrum SSTI’s, encompassing a range of clinical presentations such as deep-seated infection, a requirement for surgical intervention, the presence of systemic signs of sepsis. 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 (Panton-Valentine leucocidin) may complicate the presentation still further. Polymicrobial infection with Gram-positive and Gram-negative organisms and anaerobes may occur in diabetic foot infections and burns. Successful management of cSSTI involves prompt recognition, timely surgical drainage and debridement, intensive care if required and appropriate antibiotic therapy. The mainstays of treatment are the penicillins, cephalosporins, clindamycin, co-trimoxazole and b-lactam/b-lactamase inhibitor combinations are indicated for polymicrobial infection. A range of new agents for the treatment of methicillin-resistant Staphylococcus aureus infections have compared favourably with the glycopeptides and some have distinct pharmacokinetic advantages. These include linezolid, daptomycin, tigecycline, telavancin, ceftaroline and tedizolid.