Open fractures are often associated with high-energy trauma and have an increased risk of infection because of surrounding soft-tissue damage and the introduction of environmental contaminants that may communicate with the fracture site. The Gustilo-Anderson classification of open fractures has been used to guide prophylactic antibiotic therapy because different types of open fracture have been shown to have varying rates of surgical site infections with different combinations of pathogens. Prophylactic treatment with various classes of antibiotics, including penicillins and cephalosporins, aminoglycosides, and fluoroquinolones, has evolved over the past half century. More recently, broader spectrum agents including monobactams and glycopeptides have been used for additional coverage. Duration of antibiotic therapy remains variable between institutions, and antibiotic choice is not standardized. Coverage for nosocomial and multidrug-resistant organisms is an ongoing area of clinical research.