High-grade astrocytoma remains a significant challenge to the clinician and researcher alike. Intense study of the molecular pathogenesis of these tumors has allowed identification of frequent genetic alterations and critical core pathways in this disease. The use of novel mouse genetic tools to study the consequence of specific mutations in brain has led to the development of multiple representative genetically engineered mouse models that provided novel insights into gliomagenesis. As we learn more about the biology of high-grade astrocytoma from the study of these models, we anticipate that our improved understanding will eventually lead to greater success in clinical trials and improved outcome for patients.