In this review are discussed a small group of bone tumors that present the greatest and sometimes unresolved problems in diagnosis, not only for the clinician but also for the pathologist, even with full knowledge of the clinical and roentgenologic presentation. The following neoplastic lesions are described in detail: cartilage-forming tumors, bone-forming tumors (with special emphasis on aggressive or malignant osteoblastoma), and round-cell tumors of bone. This last group presents a special challenge to the pathologist even after histopathologic examination. Some newer, more sophisticated methods are discussed, especially those applied in the differential diagnosis of Ewing's sarcoma and tumors of neuroectodermal origin.