Meningiomas, the most common primary brain tumors, frequently harbor somatic mutations in the tumor suppressor gene NF2. To gain further insights into the etiology of these tumors, Murat Günel and colleagues performed exome sequencing of 50 meningiomas followed by targeted resequencing of selected genes in 250 additional meningiomas (Science, published online 24 January 2013; doi:10.1126/science.1233009). They found NF2 mutations in 36% of tumors and also identified recurrent mutations in TRAF7, KLF4, AKT1 and SMO. TRAF7 mutations were detected in 24% of tumors and frequently co-occurred with KLF4 mutations. Conversely, TRAF7 and KLF4 mutations were never observed in tumors with NF2 mutations. The authors also identified a recurrent activating mutation of AKT1 in 13% of tumors, as well as likely activating mutations of the Hedgehog pathway effector gene SMO in 4% of tumors. In an independent sequencing study of meningiomas, Rameen Beroukhim and colleagues report the discovery of similar activating AKT1 and SMO mutations, as well as recurrent mutations in chromatin-modifier genes (Nat. Genet. 45, 285–289, 2013). Together, these studies identify a subset of patients with meningiomas that could benefit from targeted therapies aimed at inhibiting the AKT and Hedgehog signaling pathways.