While most cases of childhood cancer are sporadic events, approximately 10% of children and adolescents diagnosed with cancer have an underlying genetic mutation that predisposes them to cancer. Cancer predisposition syndromes, such as RUNX1 familial platelet disorder, Li-Fraumeni syndrome, and Beckwith-Wiedemann syndrome, lead to an increased risk of one or more cancers over the lifetime of the individual. A better understanding of disease biology, along with genetic testing, genetic counseling and cancer surveillance, may result in improved outcomes for children with cancer predisposition syndromes.