An intravenous antibiotic, administered just before skin incision, effectively reduces the prevalence of deep wound infection. The optimal antimicrobial agent has not been determined definitively; however, a short duration of prophylaxis is recommended. Institutional compliance strategies are cost-effective and improve the timing of antibiotic administration. Also, published antimicrobial restriction recommendations are warranted because of the concern of emerging antibiotic-resistant bacteria. Specifically, restriction of vancomycin in orthopaedic surgery should be targeted critically. Supplemental antibiotic administration includes additional intra-operative antibiotic dosing, use of antibiotic-irrigant solutions, and admixture of antibiotics into acrylic bone cement or bone graft. There are no established standards or clinical guidelines for these supplemental antibiotic applications. Post-operatively, antimicrobial agents frequently are overused for various clinical scenarios and this pattern of antibiotic usage is potentially detrimental. A prophylaxis strategy for prevention of early and late hematogenous infection requires consideration of host risk factors, wound environment variables, and sources of potential bacteremia. This strategy should include deliberation of the cost-effectiveness, efficacy, and complications associated with routine use of antibiotics. Advisory statements for elective procedures, which potentially may cause bacteremia, are being developed and additional research is required for this area of antimicrobial agent prophylaxis.