Biallelic NF2 gene inactivation is common in sporadic and in neurofibromatosis type 2 (NF2)-related meningiomas. We show that, beginning at four months of age, thirty percent of mice with arachnoidal cell Cre-mediated excision of Nf2 exon 2 developed a range of meningioma subtypes histologically similar to the human tumors. Additional hemizygosity for p53 did not modify meningioma frequency or progression suggesting that Nf2 andp53 mutations do not synergize in meningeal tumorigenesis. This first mouse model initiated with a genetic lesion found in human meningiomas provides a powerful tool for investigating tumor progression and for the preclinical evaluation of therapeutic interventions.