Surgical site infections remain a significant contributor to postoperative morbidity and mortality. It is estimated that 500,000 patients suffer from this complication annually. Among other interventions, appropriate administration of prophylactic antibiotics has been shown to decrease the risk of perioperative infections. The goal of prophylactic antibiotic administration is to decrease the risk of contamination of the wound from skin flora in the case of clean procedures, and to add coverage of organisms that are anticipated to contaminate the surgical field, as in open bowel procedures. The purpose of this review is to summarize the guiding principles of perioperative antibiotic administration including selection, timing, redosing, and discontinuation. In addition, special topics including likely organisms for classes of surgical procedures, endocarditis prophylaxis, and management strategies for patients with allergies will be reviewed.