Positron emission tomography (PET)–computed tomography (CT) is a useful device in identifying musculoskeletal lesions that require biopsy. It can be used to localize the primary lesion, identify a site to biopsy, and evaluate metastatic lesions that require follow-up biopsies. Not all malignant tumors have hypermetabolic activity, and there are many benign lesions and physiologic processes that do have increased F-18 fluorodeoxyglucose uptake. Knowledge of these issues is important when reviewing PET-CT and directing subsequent musculoskeletal biopsies.