Total joint arthroplasty (TJA), the implantation of an artificial joint replacement, has become a relatively commonly practiced operation in many parts of the world. The most common reasons for performing a TJA are to restore mobility and alleviate symptoms of osteoarthritis, and reconstruction after fracture. The procedure is generally well tolerated and successful; however, periprosthetic joint infection (PJI) is the most dreaded complication. In this chapter, we will provide an overview of PJI from the perspective of an orthopedic surgeon, with the aim of providing an insight into the challenges and unresolved issues that may in the future be addressed by basic science and innovations in biomedical engineering. We describe the pathophysiology of acute and chronic PJI, the difficulties in diagnosing PJI, and the current treatment concepts, including both surgery and antibiotic therapy. Finally, we will provide an overview of the innovations in the field that may soon be translated to the clinic.