High-risk pediatric brain tumors constitute the leading cause of cancer death in children and despite the improvement of diagnostic and therapeutic approaches children with these malignancies have a very poor prognosis. Thus, it is clear that the management of these malignancies is suboptimal and novel targeted therapeutic strategies are required. Recently, a cancer stem cell population has been found responsible for the initiation of adult and pediatric brain tumors and may constitute the cellular basis for the resistance of these tumors to chemotherapy and radiotherapy and a more reliable model to study these malignancies. One of the approaches used to design novel, rational, and effective treatments directed against the molecular defects of these tumors involves the use of oncolytic adenoviruses. Our group previously reported the anti-glioma effect of the tumor-selective adenovirus, Delta-24-RGD engineered to selectively replicate in cells that harbor an abnormal RB pathway, a hallmark of cancer. We hypothesize that a targeted oncolytic adenovirus design to target not only the bulk of the tumor but also the BTSCs population, which account for resistance and recurrence, may constitute a significant improvement of the prognosis and quality of life of patient with pediatric brain tumors. Since the percentage of BTSCs would vary along the different pediatric brain tumors this strategy will be likely to be used in combinations, to maximize clinical impact and to minimize opportunities for resistant cancer cells to emerge. Consequently, we shall evaluate the cytotoxic effect of Delta-24-RGD in combination with temozolomide. Importantly, Delta-24-RGD in combination with chemotherapy would avoid the use of radiotherapy which, in turn, will prevent the subsequent loss of cognitive function without compromising disease control and thus, improving the overall quality of life for these children.