Glioblastoma, the most common primary malignant brain tumor in adults, remains a challenging disease with no current cure. A main reason for our lack of significant progress in this cancer is the profound heterogeneity of these tumors—among tumors in different patients and even among cancer cells in an individual patient. We are particularly interested in an important subpopulation of glioblastoma cells called tumor-initiating cells (also cancer stem cells), which are found in all glioblastoma tumors and are thought to drive tumor growth and treatment resistance. In this project, using gene-editing techniques and human neural stem cells, we will model the major genetic subtypes of glioblastoma and identify how specific gene mutations give rise to tumor-initiating cells. In this manner, we will be able to understand the major differences and common features among the different genetic subtypes of human GBM. The long-term goal of this project is to develop individualized therapeutic strategies based on tumor genetics, which will potentially lead to novel, durable treatments for glioblastoma patients.