Medulloblastoma is the most common malignant pediatric brain tumor. Although significant progress has been made in the treatment of medulloblastoma patients over the past several decades, the five-year disease-free survival for high-risk patients, characterized by metastatic dissemination at presentation or significant post-operative residual tumor, remains relatively poor (25-40%). Group C medulloblastoma has by far the worst prognosis with a 5-year survival probability of approximately 30% regardless of stage. Current therapeutic modalities, in particular ionizing radiation (IR), have significant long-term side-effects within the pediatric population. Enhancement of current therapies through targeted radiosensitization may allow for IR dose reduction and lead to decreased late radiation-induced sequelae. A bioinformatics approach was employed to select a number of candidate radioresistance genes that are preferentially expressed in group C medulloblastoma tumors. Candidate genes were screened using focused RNA interference to assay for sensitization to ionizing radiation using primary cell cultures derived from group C tumors. We have identified and validated the antiapoptotic gene Bcl-XL as an effective target for the radiosensitization of medulloblastoma group C tumors through this approach. Radiosensitization of both sonic hedgehog (SHH) and group C cell lines was achieved in vitro with increasing doses of the Bcl-2 family small molecule inhibitor, ABT-263 (MW = 974 Da). After a 24 hour drug pre-treatment followed by irradiation (up to 9 Gy), a dose enhancement factor (DEF) after 40% cell death of 1.7 for UW228 (SHH) and 2.2 for D425MED (group C) cell lines was obtained. Group C cells were significantly more sensitive to treatment with 50 fold less drug required (10μM ABT-263 for the SSH subgroup vs. 200nM ABT-263 for group C). Similarly, siRNA targeting Bcl-XL was able to achieve a DEF of 1.9 in UW228 cells. A murine model utilizing a paramagnetic gadolinium-based nanoparticle delivery system to bypass the BBB is currently being developed to test ABT-263 in vivo as an effective radiosensitizer of human group C medulloblastoma tumors. In summary, radiosensitization of group C tumors is expected to be useful in improving local control and survival outcomes in patients with more aggressive subtypes of medulloblastoma. In the future, pre-clinical data generated from this approach will provide a rationale for the design of an early-phase clinical trial in order to test the safety and efficacy of pharmacological Bcl-family inhibition with concurrent radiation in the treatment of patients with group C medulloblastoma.