Intracystic IFNα proved to be a safe and effective option in the multimodal management of cystic craniopharyngioma (CRF). In our institutional experience, controversial cases have arisen concern and unanswered questions, that are becoming more common with the availability of new target therapies for other brain tumors. Reliable criteria to define the response to treatment should be defined. Additionally, the best timing of surgical resection after target therapy is not clear. Surgery is postponed in case of favorable response, but tumor relapse may present a different architecture eventually increasing surgical morbidity. Finally, in case of good response to the target therapy a close follow-up is required, since rebound may occur in exceptional cases. These data should represent the benchmark for future studies using either systemic administration of IFN or other intracystic drugs.