Uncomplicated skin infections account for almost 200 million physician-office visits in the USA annually. Treating these infections is estimated to cost in excess of US$350 million each year. The primary etiology of these infections is Staphylococcus aureus, over 60% of which is estimated to be methicillin resistant across the USA. Therapeutic options include incision and drainage in combination with antimicrobial therapy, which may be oral, topical or occasionally parenteral. Because the effectiveness of the current oral options, such as beta-lactams and other classes, is being eroded due to acquired resistance, older, untested agents such as trimethoprim-sulfamethoxazole or clindamycin are often being used. Thus, topical approaches may offer effective, localized, well-tolerated alternatives to the systemic regimen. However, their value in the management of uncomplicated skin infections is not yet clearly defined. This literature review discusses various topical antibiotic treatment options for uncomplicated skin infections, including over-the-counter and prescribed regimens.