The neurofibromatoses are a group of three heterogeneous disorders that include neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), and schwannomatosis. NF1 is the most common of these three conditions, and represents one of the most frequently diagnosed cancer predisposition disorders involving the nervous system. While NF1 primarily affects the central and peripheral nervous system, multisystem involvement is the rule, with dermatologic, cardiovascular, gastrointestinal, and orthopedic affectation often reported. Importantly, NF1 is a disorder of heterogeneity, such that affected individuals can be variably affected, even within the same family. This heterogeneity also presents significant challenges to the actualization of effective treatments. However, recent studies aimed at understanding the role of the NF1 protein (neurofibromin) as a tumor suppressor have revealed that this profound level of clinical heterogeneity may reflect tissue and region-specific effects, sexually dimorphic influences, and the contribution of germline genetics and genomics. With the availability of accurate preclinical Nf1 small-animal models, human induced pluripotent stem cells, and an efficient clinical trials consortium, we are now uniquely positioned to identify and efficiently evaluate promising therapies for NF1-related medical problems.