Pediatric cancers are not the equivalent of adult cancers occurring at a younger age and the prospect of immunotherapy in children has not been received with the same enthusiasm as in the adult setting. Although most pediatric malignancies are considered immunologically cold, we are learning more about PD-L1 expression, tumor mutational burden, and microsatellite instability in several pediatric cancers. The side effects of immunotherapy are an important consideration. Immune checkpoint inhibitors (ICIs) engender a unique constellation of inflammatory toxicities known as immune-related adverse events (irAEs). Three early-phase trials—KEYNOTE-051, iMATRIX, and ADVL1412—were the first to describe irAEs in pediatric patients and ICIs were well tolerated. There was concern about unknown late irAEs in pediatric patients, as they have much more time to develop than in adult or elderly patients. Academic clinicians, biopharmaceutical companies, and parents’ advocates concluded that no benefit could be expected from further monotherapy trials employing other ICIs with the same mechanism of action until more scientific knowledge becomes available. On the other hand, ICIs could be useful in combination with other therapies to prevent the functional inactivation of several pathways in the hostile microenvironment. Future clinical studies on ICIs in children need to build on strong biological premises, taking into account the distinctive immunobiology of pediatric cancers vis-à-vis ICI-responsive adult cancers. We need to gain and share experiences of new therapies for managing pediatric patients with cancer, clarifying to what extent we can extrapolate the data obtained in adults.