Glioblastoma (GBM), the most common and deadly form of primary brain cancer in adults. After diagnosis, GBM patients undergo standard therapy, including surgery, chemotherapy and radiation therapy. Unfortunately, disease relapse is inevitable and patients face a median survival of less than 15 months. A small population of tumor cells, known as brain tumor initiating cells (BTICs), have been shown to resist standard therapy and lead to relapse. Using a multi-pronged approach, we are developing novel and rational combinatorial therapies against treatment-resistant GBM BTICs. We begin by identifying novel and rational combinatorial therapies that can be administered alongside standard therapy to GBM patients. In our arsenal of therapies, we are developing a GBM-targeted immunotherapy that harnesses and redirects the immune system to target BTICs. Together, our work aims to characterize and develop therapies against GBM BTICs to alleviate tumor burden and increase patient survival.