Li-Fraumeni syndrome is a rare yet serious hereditary cancer predisposition syndrome, marked by a significant early-life increased risk of developing cancer. Primarily caused by germline mutations in the TP53 tumor suppressor gene, Li-Fraumeni syndrome is associated with a wide range of malignancies. Clinical management of Li-Fraumeni syndrome could be challenging, especially the lifelong surveillance and follow-up of patients which requires a multidisciplinary approach. Emerging insights into the molecular and clinical basis of Li-Fraumeni syndrome, coupled with advances in genomic technologies and targeted therapies, offer promise in optimizing risk assessment, early detection, and treatment strategies tailored to the unique clinical and molecular profiles of affected individuals. This review discusses Li-Fraumeni syndrome in more depth, reviewing molecular, genomic, epidemiological, clinical, and therapeutic aspects of this disease.