Antibiotic prophylaxis can be given to prevent surgical site infection or to avoid bacterial infective endocarditis and prosthetic joint infections as a result of bacteremia following surgery. Although prophylactic antibiotics are rarely warranted for clean dermatologic surgery, there is increasing support in the literature for their judicious use for selected high-risk cases. This article discusses the host co-morbidities, wound characteristics, body sites, and complex surgical procedures associated with increased dermatologic surgical site infection and goes on to review the evidence for and against antibiotic prophylaxis in its various forms. Updated guidelines for prevention of infective endocarditis and prosthetic joint infection following dermatologic surgery are also outlined.