Medulloblastoma is a metastatic paediatric brain tumour arising in the cerebellum. It is classified into four major subgroups based on clinical and molecular profiles and current standard of care is to treat patients similarly regardless of classification. The clinical interventions of surgery, chemo- and radiotherapy can result in cures buts come at a price not obvious by the reported survival statistics due to the collateral damage of healthy tissue by these treatments, which negatively impact patient quality of life. Using high-throughput, cell-based assays human medulloblastoma cells (n=6) were screened against a library of approximately 3200 compounds. Fifty effective compounds were identified and further in vitro assessment identified several drugs that enhanced the cytotoxic activity of the clinically-used therapeutic: cyclophosphamide (CPA). Cell cycle checkpoint kinase (CHK1/2) inhibitors (CHKi), were further assessed in vivo using mice bearing intracranial implants of human medulloblastoma cells. When combined with DNA-damaging chemotherapeutics, CHKi treatment reduced tumour burden as measured by IVIS imaging and significantly increased survival of tumour-bearing animals. Immunohistochemical assessment of tumours showed the combination treatment significantly decreased tumour proliferation and significantly induced apoptosis compared with controls. These data demonstrate our experimental approach has robustly identified effective new therapies for paediatric medulloblastoma, and our findings strongly suggest CHK inhibitors have promising potential to improve treatments for this disease.