TheNF2tumor suppressor gene is a frequent somatically mutated gene in mesothelioma, with 30%–40% mesotheliomas showingNF2inactivation.NF2encodes merlin, a member of the ezrin, radixin, and moesin (ERM) family of proteins that regulate cytoskeleton and cell signaling. Recent genome analysis revealed thatNF2alteration may be a late event in mesothelioma development, suggesting thatNF2mutation confers a more aggressive phenotype to mesothelioma cells and may not be directly caused by asbestos exposure. The Hippo tumor-suppressive and mTOR prooncogenic signaling pathways are crucial cell-signaling cascades regulated by merlin. Although the exact role and timing ofNF2inactivation in mesothelioma cells remain to be elucidated, targeting theNF2/merlin-Hippo pathway may be a new therapeutic strategy for patients with mesothelioma.