Infection after a total knee arthroplasty is an infrequent but serious complication that can have devastating consequences. Infection carries a risk of significant morbidity, and the cost of treatment can be a substantial burden to the health care system. Eradication of infection can be very difficult. Prevention of infection remains the ultimate goal. Identification of host risk factors, careful patient selection, and optimization of the wound environment and the operating room remain some of the core fundamental steps that help minimize the overall incidence of infection. Although the exact role of each of these risk factors in a clinical setting can be debatable, a multidisciplinary approach incorporating all known and established methods of infection control can help to minimize the incidence of infection following total knee arthroplasty.