Antimicrobial prophylaxis has become common practice across most surgical disciplines, including fracture care. The perioperative administration of antibiotics is beneficial in reducing infections following the fixation of closed fractures. It should be begun within 1 hour before incision and not continued for more than 24 hours postoperatively. For open fractures, antibiotics provide benefit in the setting of wound contamination, and should be begun as soon as possible after injury, with the most effective agent for this being a broad-spectrum, first-generation cephalosporin. Coverage should be broadened in cases of severe contamination. Similarly, in facilities in which methicillin-resistant Staphylococcus aureus infections are a known problem, the use of vancomycin may be justified for prophylaxis. However, because the use of antibiotics is not benign and can have associated toxicities and allergies, and may also be met with antimicrobial resistance, the surgeon should be cognizant of the indications for and duration of administration of any antibiotic used in the care of fractures.