Most medical students are educated to mention periosteal reactions and the first reaction is malignancy. This is the description of a classic case on the medical exam. However, if one is a bone oncology specialist, one would not think so. There are many types of periosteal reactions, some are benign, some are inflammatory, some are highly malignant, and some are low-grade malignancies. (1) If the periosteal reaction presents as a horizontal line and is lateral to the bone cortex and has a very narrow translucent gap in between, it often represents an early presentation or an inflammatory condition (e.g., eosinophilic granuloma). (2) Substantial periosteal reaction, which is smooth, dense, and parallel to the longitudinal axis of the bone, often indicates a benign tumor. It is often seen in osteoid osteoma, chondrosarcoma, etc. (3) Multi-layered and onion skin-like tumors generally indicate a higher degree of malignancy. For example, Ewing’s tumor. However, it is occasionally seen in chronic infections, which usually do not have soft tissue masses. (4) If the tumor is perpendicular to the longitudinal axis of the bone tissue and is needle-like or sunlight-like, it is basically a tumor with a high degree of malignancy. (5) Faint periosteal reaction with the presence of osteoporotic-like changes. If soft tissue masses are present, the tumor is considered to be highly malignant. If there is no soft tissue mass, acute inflammation is considered as a possibility. The periosteal reaction is generally pathologically divided into three layers of structure: the most superficial layer is the proliferative layer, which is not shown on plain X-rays; the middle layer is the step-bearing mature trabecular layer; and the innermost layer is the Harvard’s canal. A more mature periosteal reaction will exist with a gap between the bone tissue. Theoretically, the periosteal reaction is a manifestation of value-added differentiation and function of osteoblasts, mesenchymal stem cells, and vascular endothelial cells in response to inflammatory stimuli. During inflammation and tumor invasion, both produce local release of inflammatory factors and cellular value-added responses. It is the significance of the periosteal reaction to back-extrapolate and diagnose disease based on different morphologies and structures. This process requires experience, as well as learning and frequent summaries.