Li-Fraumeni syndrome (LFS) is an inherited cancer syndrome that affects a small percentage of the population worldwide. LFS is characterized by multiple cancers in affected family members and is devastating to all diagnosed patients and their relatives. A link has been identified between LFS and mutations in the tumor-suppressor gene that encodes for the P53 protein, and much research has been done on the effect of this mutation in tumorigenesis. However, the natural history of the disease has no definitive pathway, and additional research is under way. LFS is rare, can present in many ways, requires complex management, and has tumors that often first present in childhood. Therefore, pediatric nurse practitioners should be aware of LFS as a potential differential diagnosis in patients with multiple tumors, certain rare tumors, or most importantly, a family history notable for multiple early-onset cancers.