Malignant glial tumors (anaplastic astrocytomas and glioblastomas multiforme) arise mostly either from the progression of low grade precursor lesions or rapidly in a de novo fashion and contain distinct genetic alterations. There is, however, a third subset of malignant gliomas in which genetic lesions remain to be identi®ed. Following surgical resection, all gliomas appear to have an inherent tendency to recur. Comparative molecular analysis of ten primary malignant gliomas (three anaplastic astrocytomas and seven glioblastomas multiforme) with their recurrences identi®ed two distinct subgroups of recurrent tumors. In one group, primary tumors harbored genetic aberrations frequently associated with linear progression or de novo formation pathways of glial tumorigenesis and maintained their genetic pro®les upon recurrence. In the other subset with no detectable known genetic mutations at ®rst presentation, the recurrent tumors sustained speci®c abnormalities associated with pathways of linear progression or de novo formation. These included loss of genes on chromosomes 17 and 10, mutations in the p53 gene, homozygous deletion of the DMBTA1 and p16 and/ or p15 genes and ampli®cation and/or overexpression of CDK4 and alpha form of the PDGF receptor. Recurrent tumors from both groups also displayed an abnormal expression pro®le of the metalloproteinase, gel A, and its inhibitor, TIMP-2, consistent with their highly invasive behavior. Delineation of the molecular di erences between malignant glioblastomas and their subsequent recurrences may have important implications for the development of rational clinical approaches for this neoplasm that remains refractory to existing therapeutic modalities.