Recent advances in our understanding of the molecular genetic mechanisms underlying diffusely infiltrating brain neoplasms have important implications for the classification and therapy of these tumors. Traditionally, primary brain tumors have been classified histologically; however, it is now clear that tumors within a single histologically defined category are heterogeneous from a molecular genetic perspective. Furthermore, many new experimental therapeutic strategies directed against these almost invariably fatal tumors are aimed at molecular rather than histologic abnormalities. Consequently, the classification of these tumors is in the process of being re-evaluated as underlying molecular genetic mechanisms continue to be elucidated. This review covers traditional histologic based classification of infiltrating glial neoplasms together with molecular abnormalities of these tumors involving p53, epidermal growth factor receptor, the retinoblastoma pathway, platelet derived growth factor receptor, genetic losses on chromosome 10, and loss of heterozygosity on chromosomes 1p and 19q. The contribution of these molecular genetic abnormalities to the classification and therapy of these tumors is discussed. Although at the present no molecular system for the classification of brain tumors has been generally accepted, microarray technologies offer the exciting prospect of practical molecular classification in the future.