Primary brain tumors consist of neoplasms with varied molecular defects, morphologic phenotypes, and clinical outcomes. The genetic and signaling abnormalities involved in tumor initiation and progression of the most prevalent adult primary brain tumors, including gliomas, meningiomas, and medulloblastomas, are described in this article. The current understanding of the cell-of-origin of these neoplasms is reviewed, which suggests that the malignant phenotype is propelled by cells with stem-like qualities. A comprehensive understanding of the molecular basis of transformation and the cell-of-origin of these neoplasms will enable the formulation of more targeted treatment alternatives that could improve survival and quality of life.