Osteogenic sarcoma (osteosarcoma) is the most common primary tumor of bone. It accounts for approximately 19% of all malignant tumors of the bone. Of all the molecular targets altered during the genesis of osteosarcoma, the retinoblastoma gene (RB1) shows the highest frequency of inactivation. Published data from human osteosarcoma tumors and in vivo and in vitro model systems support a role for the retinoblastoma gene family in bone development and tumorigenesis. Although a variety of bone tumors, depending on the cell of origin, including osteoclasts or osteoclast-like cells, chondroblasts, and fibroblasts, are described, for the purpose of this review we will focus primarily on the tumors arising from the osteoblast lineage.