Nearly 700,000 hip and knee arthroplasties are performed annually in the United States. Although the results in most cases are excellent, implants do fail. Complications like heterotopic ossification, fracture, and dislocation are now relatively rare and easily diagnosed. Differentiating aseptic loosening, the most common cause of prosthetic joint failure, from infection, is important because their treatments are very different. Unfortunately, differentiating between these 2 entities can be challenging. Clinical signs of infection often are absent. Increased peripheral blood leukocytes, erythrocyte sedimentation rate, and C-reactive protein levels are neither sensitive nor specific for infection. Joint aspiration with Gram stain and culture is the definitive diagnostic test. Its specificity is in excess of 90%; its sensitivity is variable, however, ranging from 28% to 92%. Plain radiographs are neither sensitive nor specific and cross-sectional imaging modalities, such as computed tomography and magnetic resonance imaging, can be limited by hardware-induced artifacts. Radionuclide imaging is not affected by orthopedic hardware and is the current imaging modality of choice for suspected joint replacement infection. Bone scintigraphy is sensitive for identifying the failed joint replacement, but cannot be used to determine the cause of failure. Neither periprosthetic uptake patterns nor performing the test as a 3-phase study significantly improve accuracy, which is only about 50-70%. Thus, bone scintigraphy typically is used as a screening test or in conjunction with other radionuclide studies. Combined bone gallium imaging, with an accuracy of 65-80%, offers only modest improvement over bone scintigraphy alone. Presently, combined leukocyte/marrow imaging, with approximately 90% accuracy, is the radionuclide imaging procedure of choice for diagnosing prosthetic joint infection. In vivo leukocyte labeling techniques have shown promise for diagnosing musculoskeletal infection; their role in prosthetic joint infection has not been established. (111)In-labeled polyclonal immunoglobulin lacks specificity. (99m)Tc-ciprofloaxicin does not consistently differentiate infection from aseptic inflammation. (18)F-fluorodeoxyglucose positron emission tomography has been extensively investigated; its value in the diagnosis of prosthetic joint infection is debatable.