There is no single intervention that will eliminate infection risk for total knee arthroplasty (TKA) individuals. Undoubtedly, some individuals are more prone than others to infection, but even the healthiest are at risk. Based on current evidence, TKA surgeons should utilize many strategies in their practice to diminish the risk of surgical site infection, although debate exists as to what constitutes best practice. Infection prevention in TKA needs a multifaceted approach that includes patient bacterial decolonization, avoidance of anemia, blood transfusion, perioperative patient warming, laminar flow, space suits, careful skin antisepsis, povidone-iodine wound lavage, and triclosan-coated sutures. However, important differences still exist in the employment of periprosthetic joint infection preventive measures across different geographic areas.