Cancer is a genetic disease—with the role of somatic mutations in tumor cells well-described in all cancer types. The role of germline genetic changes has also been long-recognized in familial cancer syndromes, such as familial breast cancer—but the important role of germline mutations in cancer predisposition genes (CPGs) in the development of seemingly sporadic cancers is also becoming increasingly apparent. This chapter explores the current and evolving knowledge of CPG germline mutations in childhood and adolescent cancers. Current estimates indicate that at least 10% of all children presenting with cancer carry a germline mutation in a CPG. These changes are usually either a “first hit” in a tumor suppressor gene—with a cell later acquiring a second, somatic mutational hit, enabling tumorigenesis—or a germline change which increases DNA mutation rate, thereby increasing the chance of random mutations occurring. Identification of mutations by germline sequencing should be integrated into routine clinical care for all children presenting with cancer, as it allows precise molecular classification, guiding of therapeutic strategies (including targeted therapies and pharmacogenomics) and appropriate genetic counselling/surveillance within the family. This chapter explores the key cancer syndromes associated with pediatric solid cancers, including central nervous system tumors, bone tumors, and other common malignancies, such as Wilms’ tumor and neuroblastoma. In each cancer type, the associated familial syndromes are explored, as well as the sporadic germline high-penetrance genetic risk factors. The understanding of pediatric genetic cancer predisposition is a rapidly emerging field, and as knowledge expands, it is hoped that increased understanding of the genetic etiology of children’s cancer translates into improved clinical outcomes for affected children.