With increasing antibiotic resistance reported worldwide, there is a great interest in the development of new antibacterial agents for the treatment of severe skin and skin structure infections (SSSIs). SSSIs mainly involve Grampositive pathogens. Although many of older antibiotics remain effective, new drug development remains crucial owing to the increase in drug resistance among the major Gram-positive pathogens. Since 1999 new antibacterial agents have entered the market or are being evaluated in clinical trials for the treatment of SSSIs. These agents have novel mechanism of action and sufficient improvements in potency to overcome resistance. Linezolid, quinupristin-dalfopristin, daptomycin and tigecycline have been approved by the FDA for the treatment of SSSIs. Other antimicrobials (dalbavancin, oritavancin, telavancin) are currently in clinical development for this indication. This review focuses on the chemistry, microbiology, pharmacology, clinical efficacy and safety of several novel antibacterial agents for the treatment of SSSIs.