The p53 gene is the most commonly altered gene in a multitude of human cancers. The alterations can be acquired somatically or transmitted through the germ-line. Bone and soft tissue sarcomas are frequently found to have acquired abnormalities in the p53 and mdm-2 genes. In soft tissue sarcoma, the amplification of the mdm-2 gene and the binding of its oncogene product to wild-type p53 protein functionally inactivates normal p53-regulated growth. Inherited mutations of the p53 gene are associated with the rare Li-Fraumeni familial cancer syndrome. Various tumor types arise in these families, with sarcomas of the bone and soft tissues and carcinoma of the breast being the most frequently observed. Transgenic mice with highly expressed mutated p53 have a higher incidence of tumors, including predominantly osteosarcomas and soft tissue sarcomas. In close similarity with the Li-Fraumeni syndrome, homozygously p53-null mice (transgenic mice carrying two non-functional p53 allele) are developmentally normal however they are susceptible to spontaneous tumor formation. This article reviews briefly the structure, function, and dysfunction of the p53 tumor-suppressor gene with particular focus on its role in the development of bone and soft tissue sarcoma.