Biopsy is a key step in the diagnosis of bone and soft tissue tumors. An inadequately performed biopsy may fail to allow proper diagnosis, have a negative impact on survival, and ultimately necessitate an amputation to accomplish adequate margins of resection. Poorly performed biopsy remains a common finding in patients with musculoskeletal tumors who are referred to orthopaedic oncology centers. The principles by which an adequate and safe biopsy of musculoskeletal tumors should be planned and performed are reviewed, and the surgical approach to different anatomic locations is emphasized.