Neurofibromatosis type 1 (NF1) is a monogenic but highly multisymptomatic disorder that affects 1:2500 individuals and results from mutations in the Nf1 tumor suppressor gene. Nf1 encodes Neurofibromin (Nf1), a large multifunctional protein, preferentially expressed in the central and peripheral nervous system, crucial for regulating multiple signaling pathways. Although typically considered a tumor predisposition syndrome, NF1 is also associated with broad cognitive and behavioral presentations, including impaired learning, attention deficit hyperactivity disorder, autism spectrum disorder, social/communicative disabilities and disturbed sleep. Uncovering the molecular and cellular mechanisms whose perturbation underlies these deficits, requires appropriate animal models emulating human phenotypes. Therefore, our main aim is to use the two main NF1 model systems, Drosophila and mice, harboring specific Nf1 mutations associated with behavioral/cognitive symptoms in patients and similar deficits in the models, to elucidate the determinants of these phenotypes. Loss of the highly conserved Drosophila dNf1 ortholog mimics human NF1 pathology, causing reduced size, impaired learning, synaptic defects, behavioral inflexibility, and abnormal activity and sleep patterns. Furthermore, particular Nf1 point mutations are associated with specific behavioral deficits that implicate distinct molecular mechanisms than those affected upon total Nf1 loss. Our evidence thus far, suggests that different Nf1 mutations may impact distinct functions of the protein, possibly in a cell-type-specific manner, thus contributing to the variability observed in NF1-related pathologies. Revealing the determinants of these phenotypes in both animal models will contribute significantly to the development of novel, potentially personalized ameliorative strategies for these defects.