Glioblastoma (GBM) is the most aggressive malignant primary brain cancer, with an incidence rate of 3.9 per 100,000 persons in the United States and a median age of 64 years. GBM has an average life expectancy of one year. This is mostly due to the highly muted genome of GBM, which is characterized by the deregulation of many key signaling pathways involving growth, proliferation, survival, and apoptosis. In this review, I try to summarize the molecular mechanisms that have led to the GBM and discuss the potential therapeutic strategies and approaches.