Activation of the p21-ras signaling pathway from aberrantly expressed receptors promotes the growth of malignant human astrocytomas. We developed a transgenic mouse astrocytoma model using the glial fibrillary acidic protein (GFAP) promoter to express oncogenic V(12)Ha-ras, specifically in astrocytes. The development of GFAP-immunoreactive astrocytomas was directly proportional to the level of V(12)Ha-ras transgene expression. Chimeras expressing high levels of V(12)Ha-ras in astrocytes died from multifocal malignant astrocytomas within 2 weeks, whereas those with moderate levels went to germ-line transmission. Ninety-five percent of these mice died from solitary or multifocal low- and high-grade astrocytomas within 2-6 months. These transgenic astrocytomas are pathologically similar to human astrocytomas, with a high mitotic index, nuclear pleomorphism, infiltration, necrosis, and increased vascularity. Derivative astrocytoma cells are tumorigenic upon inoculation in another host. The transgenic astrocytomas exhibit additional molecular alterations associated with human astrocytomas, including a decreased or absent expression of p16, p19, and PTEN as well as overexpression of EGFR, MDM2, and CDK4. Cytogenetic analysis revealed consistent clonal aneuploidies of chromosomal regions syntenic with comparable loci altered in human astrocytomas. Therefore, this transgenic mouse astrocytoma model recapitulates many of the molecular histopathological and growth characteristics of human malignant astrocytomas in a reproducible, germ-line-transmitted, and high-penetrance manner.