Neurofibromatosis type 1 (NF1) is a dominant genetic disorder characterized by multiple benign and malignant nervous system tumors, and by learning defects in 45% of children with NF1 mutations. Studies of neurofibromin, the protein encoded by NF1, have focused on its functions in tumorigenesis and regulation of Ras activity; however, Drosophila NF1 regulates both Ras and cyclic AMP (cAMP) pathways. Expression of a human NF1 transgene rescued cAMP-related phenotypes in NF1 mutant flies (small body size and G protein–stimulated adenylyl cyclase (AC) activity defects), and neuropeptide– and G protein–stimulated AC activity were lower in Nf1^−/− as compared to Nf1^+/− mouse brains, demonstrating that neurofibromin regulates AC activity in both mammals and flies.