The causal association of germline TP53 mutations with development of cancer in individuals with the Li-Fraumeni Syndrome (LFS) cancer predisposition phenotype was initially described in 1990. Since then, technical advances in genetic and genomic sequencing, enhanced understanding of the biology of p53, creation and study of mouse models of p53 deficiency and mutant p53, and extensive annotation of the evolving clinical phenotype has improved our knowledge of this relatively rare syndrome. Several challenges remain to be overcome; these include 1) the molecular landscape of cancers associated with germline TP53 mutations is poorly understood; 2) effective means of tumor prevention and treatment are lacking; and 3) prediction of tumor type or age of onset are difficult. This lecture will examine the progress made to date in understanding the molecular and clinical aspects of the p53-LFS relationship and will explore early clues that will help address the remaining challenges.