Periprosthetic joint infection (PJI) continues to be a devastating problem in the field of total joint arthroplasty, and recent literature can be used to make the preoperative diagnosis of PJI, guide nonsurgical and surgical treatment, and provide postoperative antimicrobial management of PJI patients. The diagnosis of PJI relies on traditional serum and synovial fluid tests, with newer biomarkers and molecular tests. Surgical treatment depends on the duration of infection, host qualities, and surgeon factors, and procedures include débridement, antibiotics, and implant retention, one-stage exchange arthroplasty, two-stage exchange arthroplasty, resection arthroplasty, fusion, or amputation. Appropriate management of PJI involves coordination with infectious disease consultants, internal medicine physicians, and orthopaedic surgeons. Antimicrobial management is guided by the organisms involved, whether it is a new or persistent infection, and antibiotic suppression should be administered on an individual case basis. The goals of this instructional course lecture are to review the most relevant recent literature and provide treating physicians and surgeons with the most up-to-date armamentarium to reduce the recurrence of PJI.