Prosthetic joint infection (PJI) is a devastating complication following total joint replacement that leads to excess morbidity, mortality, and cost. This chapter has outlined effective prevention strategies that may be utilized in all phases of perioperative care. A multifaceted approach to the patient undergoing total joint replacement will have the greatest positive effect. Further study will be needed to identify and share “best practice” models that might be emulated to lower the PJI risk for all patients.