Antibiotic prophylaxis is generally administered either to prevent wound infection or to hinder the development of endocarditis. Although the use of antibiotics in certain circumstances to prevent wound infection can be straightforward, there are other circumstances in which the decision to use antibiotics is much less clear. Endocarditis prophylaxis has traditionally been based on the American Heart Association's guidelines, which do not cover dermatologic surgery. This article discusses the rationale and controversies surrounding the use of antibiotic prophylaxis for prevention of both wound infection and endocarditis, reviews the few studies that pertain to dermatology, and provides recommendations for antibiotic prophylaxis on a case-by-case basis for those who perform dermatologic surgery.