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Acute management of open fractures is associated with high morbidity and mortality. Recommended antibiotic regimens for all Gustilo-Anderson fracture grades include first-, second-, and third-generation cephalosporins. Expanded gram-negative coverage is recommended for Grade II and III fractures if a first- or second-generation cephalosporin is selected, and additional anaerobic coverage is required if the open fracture is contaminated with organic or farm-related material. Open fractures endure a high rate of bacterial contamination, and antibiotics have demonstrated effectiveness at reducing infection rates when initiated early. Provided that the expected microbial spectrum is covered, antibiotics should be selected on the basis of patient-specific factors and hospital protocols.