Percutaneous needle biopsy of lesions affecting the musculoskeletal system should be considered a routine radiologic procedure. Although relatively safe, the procedure requires expertise. An experienced radiologist and the cooperation of a skilled pathologist are essential. Consultation with the orthopedic surgeon is also important, especially when resection of the lesion is contemplated. Recent advances in imaging techniques and the availability of various cutting and trephine needles have made it easier to perform biopsies safely and accurately, even in difficult locations. The procedure obviates surgery in many instances and facilitates appropriate surgical planning in others. This review offers a pragmatic approach to percutaneous needle biopsy of skeletal lesions. It is hoped that more radiologists will be encouraged to undertake these valuable procedures.