Periprosthetic joint infection (PJI) is one of the most catastrophic and difficult to manage complications following total hip and total knee arthroplasty. As the number of total joint arthroplasties continues to increase, the burden of PJI will continue to further strain resources. As such, orthopedic surgeons consider four principles crucial in appropriately managing difficult or complex cases of PJI: identification, debridement, antibiotics, and patience. Indications and techniques for nonoperative treatment, debridement with implant retention, and one- and two-stage exchange arthroplasty are reviewed. Despite optimal care, a subset of patients will experience failure and the role of resection, fusion, and amputation is discussed. Understanding appropriate patient selection, pathogens, and improved surgical techniques should form the basis of managing PJI.