Li-Fraumeni Syndrome (LFS) is a rare, inherited disorder, which leads to a markedly increased risk of certain cancers. These cancers, such as bone and soft tissue sarcomas, breast cancer, and brain tumors, occur at younger ages in patients with LFS than in the general population. The diagnosis of LFS is made based on the personal and family history of cancers. Approximately 70% of patients with LFS have a mutation in the TP53 gene. We organized an LFS clinical research workshop November 2010 which led to the development of a family support group and an international research consortium with investigators from Europe, Australia, and North and South America. Our clinical and genetic study of LFS opened to accrual in 2011. Detailed medical history and family history questionnaires are evaluated. Eligible participants undergo cancer screening at the NIH Clinical Center. Genetic counseling and testing provided. Additional studies include investigation of genetic modifiers, and the search for the genetic causes of LFS in the 30% of clinically affected patients without a TP53 mutation. Studies of the psychosocial challenges of LFS are underway.