Malignant gliomas (MG) are highly invasive and aggressive brain tumors. Despite the current standard of care, the prognosis for patients with MG is abysmal– highlighting the need for novel, more effective treatment options to combat this aggressive disease. Oncolytic virus (OV) therapy is an advancing treatment option that harnesses tumor-selective viruses to kill cancer cells while simultaneously facilitating a systemic anti-tumor immune response. Many studies have noted synergistic effects when OV’s are combined with radiotherapy in preclinical cancer models, warranting further investigation of this multi-modal approach. Image-guided radiotherapy (IGRT) uses computer-modulated imaging techniques to precisely deliver ionizing radiation to treat cancer. Despite the precision IGRT offers, cancer cells can still be ‘missed’ due to tumor microextensions or radioresistant cell populations– such as glioma stem cells or therapy-induced senescent cancer cells –and may contribute to recurrence or progression. Here we propose to combine our mCherry-tagged mutant vaccinia virus (deltaF4L-deltaJ2R-mCherry), which exhibits tumor-selectivity due to mutations in key viral nucleotide biosynthesis genes, with IGRT executed using state-of-the-art Small Animal Radiation Research Platform (SARRP) technology. We hypothesize that combining deltaF4L-deltaJ2R-mCherry with IGRT will produce better tumor control than either modality alone, by generating additive or synergistic effects in which IGRT destroys the majority of the tumor mass while our OV seeks out and targets any remaining cancer cells that have been missed or are resistant to radiotherapy.