Approximately 8–10% of children with cancer have an underlying cancer predisposition syndrome (CPS). The most commonly mutated genes in the affected patients concern TP53, APC, BRCA2, NF1, PMS2 and RB1. A CPS should be suspected when patients present with multiple primary malignancies, a particular tumor type with a known association, a significant family history, and/or physical features consistent with a specific tumor predisposition syndrome and excessive treatment related toxicity. In these situations, referral to clinical geneticist and genetic testing should be recommended. Identifying pathogenic germline variants in cancer predisposition genes may have implications for treatment, surveillance of the patient and family members that may carry the pathogenic germline variant, as such surveillance may lead to early diagnosis of subsequent malignancies and increased survival. Psychological support and social-ethical issues are also important in approaching patients with CPSs and their families.