Biopsy continues to play a pivotal role in the management of lesions of the musculoskeletal system, especially bone tumors, for which histological type and grade guide management. Imaging-guided bone biopsy has progressed significantly with innovations in imaging guidance and interventional hardware. The high accuracy, lower costs, decreased complication rate and morbidity, and lower risk of tumor seeding as opposed to open surgical biopsy have supported imaging-guided biopsy as the preferred mode of biopsy. This chapter reviews the issues related to imaging-guided percutaneous bone biopsy.