Medulloblastoma is the most common childhood brain malignancy. Surgical resection and craniospinal irradiation followed by chemotherapy are the mainstays of treatment. Despite treatment intensification, survival has plateaued for the past two decades at around 70%. Medulloblastoma patients that relapse are essentially incurable, ergo, the best opportunity to cure medulloblastoma is during frontline therapy. Our aim is to identify novel drugs that can enhance front-line therapies and hence increase cure rates. We undertook an unbiased high-throughput drug screen which identified inhibitors of the DNA-damage response pathway as promising candidates, including kinase inhibitors targeting ATR. ATR is a key mediator of the pathway and its activation allows tumour cells to repair otherwise curative DNA damage caused by therapy. We tested the ability of an inhibitor of ATR (iATR) to interact with conventional chemotherapies and kill group 3 medulloblastoma tumour cells using in vitro drug interaction assays. iATR enhanced in vitro cytotoxicity of conventional chemotherapeutics cisplatin and cyclophosphamide as well as gemcitabine, which is currently in clinical trial. In vivo testing was using sophisticated, orthotopic mouse models of meduloblastoma. When given in combination with cyclophosphamide and gemcitabine, iATR significantly extended survival in several different group 3 medulloblastoma models, while combination with cisplatin was not as effective. We can also mimic clinical radiation protocols in our mouse models using the state-of-the-art X-rad SMART system. Preliminary results demonstrate that iATR can enhance radiation induced tumour cell apoptosis after only a single dose. Collectively, we highlight the exciting new potential of iATR as an adjuvant front-line therapy. Future studies will determine if iATR can facilitate a reduction in the dose of harmful radiation without compromising survival.