Image-guided percutaneous biopsy of musculoskeletal lesions is a safe and useful procedure for diagnosing and managing patients who have suspected bone and soft tissue lesions. Preprocedural careful planning is required, however, including completion of staging before biopsy and being absolutely certain of the biopsy track. Employment of the appropriate imaging technique to guide biopsy, needle selection, specimen handling, adopting a meticulous approach, and being aware of potential complications are advocated. Fluoroscopy, ideally biplanar, is used most often to guide biopsy in long bones. Positioning is usually more comfortable for the patient. Patient movement does not degrade image quality as severely as for CT or MR imaging. Fluoroscopy is also more widely available, is cheaper, and delivers a lower radiation dose compared with CT for the same imaging duration. Visualization of small intramedullary lesions and soft tissue component of bone tumors, however, is poor. Also, small lesions in complex-shaped bones (eg, pelvis and vertebrae) may be difficult or hazardous to access on fluoroscopic guidance. Ultrasound is used most frequently to guide biopsy of soft tissue lesions. Ultrasound also can be used for lesions on or near a bone surface, especially if there is an associated soft tissue component. CT-guided biopsy has been shown to be accurate, low in complications, cost-effective, and relatively pain-free for the patient. It has become the preferred method for biopsy of musculoskeletal lesions in most tumor treatment centers. CTF has been a practical clinical tool that facilitates effective performance of percutaneous musculoskeletal biopsies, allowing for more direct control of needle placement. The benefits of real-time imaging and increased operator needle placement control come at the cost of increased radiation dose to the patient and personnel. MRI is now the modality of choice for detecting, characterizing, and defining the anatomic extent of most musculoskeletal neoplasms. Several non randomized, retrospective case series of MRI-guided biopsies have demonstrated diagnostic yields similar to other modalities. Lack of ionizing radiation makes MR-guided biopsy desirable for pediatric and pregnant patients.