Diagnosing musculoskeletal infection is challenging and imaging procedures are part of the diagnostic workup. Although the most commonly performed radionuclide procedures include bone, gallium-67, and labeled leukocyte imaging, FDG-PET (PET/CT) is assuming an increasingly important role in the diagnostic workup of musculoskeletal infection. FDG offers advantages over conventional radionuclide techniques. PET, a high-resolution tomographic technique, facilitates precise localization of abnormalities. Semiquantitative analysis potentially could be used to differentiate infectious from noninfectious conditions and monitor response to treatment. FDG is a small molecule entering poorly perfused regions rapidly; the procedure is completed in hours not days. Degenerative changes usually show faintly increased FDG uptake. FDG uptake usually normalizes within 3-4 months following trauma or surgery. Sensitivities higher than 95% and specificities ranging from 75% to 99% have been reported in acute and subacute bone and soft tissue infection. The test is also useful for diagnosing chronic and low-grade infection because FDG accumulates in activated macrophages. No one tracer is equally efficacious in all regions of the skeleton and the utility of FDG varies with the indication. One area in which FDG imaging clearly is useful, and should be the radionuclide study of choice, is in the evaluation of spinal osteomyelitis. The test has a high negative predictive value and is a useful adjunct to MRI for differentiating degenerative from infectious end plate abnormalities. The role of FDG imaging in the evaluation of diabetic foot infection has yet to be clarified, with some investigators reporting high accuracy and others reporting just the opposite. Although initial investigations suggested that FDG accurately diagnoses lower extremity joint-replacement infection subsequent studies indicate that this test cannot differentiate aseptic loosening from infection. This is not surprising because aseptic loosening and infection both can be accompanied by an intense inflammatory reaction. A recent meta-analysis found that the sensitivity and specificity of FDG-PET for diagnosing lower extremity prosthetic joint infection was 87% and 82%, respectively, lower than what has been reported for combined leukocyte-marrow imaging over the past 30 years. Data about FDG-PET in septic arthritis are limited. FDG accumulates in inflammatory arthritis and its role for diagnosing septic arthritis likely would be limited.