Since its description by Li and Fraumeni over 40 years ago, Li–Fraumeni syndrome (LFS) remains one of the most striking familial cancer predisposition syndromes. Children and adults are affected by a wide array of cancers that occur predominantly at younger ages. This review discusses LFS, describes its association withTP53, and examines the classic and evolving definitions of the syndrome. The potential implications of multigene assessments of individuals at increased cancer risk, which have already begun to identify those with very little personal or family cancer history carrying germlineTP53mutations, are considered. Newer options in the management of individuals with LFS are also discussed, highlighting the importance of further clinical trials for cancer detection, prevention, and management. Finally, we observe how the clinical criteria forTP53mutation screening appear to be evolving as our understanding of the impact of germlineTP53mutations continues to expand.