Medulloblastoma and pineoblastoma are malignant childhood brain tumours where many patients don’t respond to existing therapy, highlighting the need for new therapeutic strategies. To evaluate the efficacy of potential new drugs, as single agents and in combination with conventional chemotherapeutics, we have developed in vitro models and multiple in vivo systems of these diseases. Overexpression of the ERBB family of tyrosine kinases is associated with poor prognosis in medulloblastoma and thus form potential target for therapy. The expression and activity of EGFR and ERBB2 were evaluated by immunoblot in two paediatric brain tumour cell lines, PER-452 (pineoblastoma) and DAOY (medulloblastoma) which had been modified to express firefly luciferase. The pan-ERBB receptor inhibitor dacomitinib effectively blocked receptor activity and downstream signalling in vitro. Moreover the drug had potent anti-proliferative effects in each cell line and was observed to synergistically interact with cyclophosphamide (CPA), a drug commonly used in treatment of these cancers, to inhibit tumour cell proliferation. Therefore dacomitinib and/or combination treatment was further evaluated in vivo in animals that had been intracranially implanted with each cell line. Using bioluminescence, tumours were monitored until well established, then animals were treated with vehicle, dacomitinib, CPA, or both. Immunohistochemical analyses of treated tumours confirmed inhibition of ERBB receptors and staining for markers of proliferation and apoptosis revealed in vivo anti-tumour activity. Despite these positive results, no overall improvement in survival was observed in medulloblastoma-bearing animals treated with these chemotherapeutics drugs. This study illustrates a unique and thorough drug evaluation pipeline, in which the efficacy of new drugs for paediatric brain tumours can be determined, enabling the exclusion of potentially ineffective treatments and prioritisation of truly beneficial novel treatments for clinical trial.