Osteosarcoma is one of the most common primary non-hematologic bone tumors present in both children and adults. The etiology of most cases of osteosarcoma is unknown although a genetic predisposition is suspected. Most osteosarcomas are diagnosed before the age of 20, where the pathology is likely distinct from osteosarcoma diagnosed over the age of 60, which is associated with bone diseases such as Paget disease or Rothmund-Thomson syndrome. Although rare, osteosarcoma is a complication in survivors of childhood cancers treated with radiation therapy. Tumors from patients diagnosed early in life are reported to have a broad range of genetic and molecular factors that are potential targets in disease formation. However, RB1 and/or TP53 mutations are consistently detected in the majority of osteosarcomas. This chapter will focus on understanding the potential links between disruption of genetic components in osteogenic differentiation and osteosarcoma.