The emergence of community-associated methicillin-resistant Staphylococcus aureus (MRSA) and glycopeptide tolerance in S. aureus has underlined the importance of the newer anti-MRSA agents, particularly in the management of complicated skin and soft tissue infections (cSSTIs). The novel cyclic lipopeptide antibiotic daptomycin shows marked in vitro cidality against MRSA compared with both vancomycin and linezolid. Although comparative studies in cSSTIs have demonstrated non-inferiority with vancomycin and semi-synthetic penicillins, data from both clinical trials and observational studies suggest in vivo cidality as evidenced by rapid resolution of clinical signs of local inflammation and reduced duration of therapy. Overall success in SSTI post-marketing studies is >90%, and >88% in MRSA-infected patients, with no difference in the outcome observed between those with complicated versus uncomplicated infections. When used at licensed doses (4-6 mg/kg), daptomycin is safe and effective in SSTIs with significant muscle toxicity occurring in only 0.4% to 2.5% of patients. Clinical failure in daptomycin-treated SSTIs is associated with severity of infection (creatinine clearance <30 mL/min, intensive care unit stay and sepsis syndrome). Higher dosing at 6 mg/kg (with increased dosing interval in renal failure) should be considered in such patients as well as those at risk of bacteraemia, osteomyelitis, diabetic foot infection and in situations where there is more rapid drug clearance, such as infections complicating intravenous drug use and thermal burns. Once-daily dosing allows ease of use in both hospital and outpatient settings and may facilitate early discharge or avoided admission in some patient groups with SSTIs. Clinical experience to date suggests potential economic advantages associated with earlier hospital discharge and shorter duration of therapy, although further detailed cost-effectiveness comparisons are required to validate these observations in different healthcare settings.