DEFECTS in the NF1 gene have been implicated in the inherited disorder neurofibromatosis type 1, which is characterized by several developmental abnormalities including an increased frequency of benign and malignant tumours of neural crest origin (neuro-fibromas and neurofibrosarcomas respectively) 1. The NF1 gene encodes a ubiquitous protein homologous to p!20 GAP, the GTPase-activating protein (GAP) for the products of the ras proto-oncogenes2-6. When expressed in non-mammalian systems, the region of the NF1 gene homologous to p!20GAP produces a protein with GAP-like activity7-9. Here we present evidence that the ras proteins in malignant tumour cell lines from patients with type 1 neurofibromatosis are in a constitutively activated state, as judged by the guanine nucleotide bound to them, and are necessary for cellular proliferation. These cells contain P21rasand p120GAP that are both functionally wild type, but barely any functional NF1 protein. Our results show that the NF1 protein is normally essential for correct negative regulation of ras proteins in the cell, even in the presence of normal p120GAP, and they support the hypothesis that NF1 is a tumour-suppressor gene whose product acts upstream of ras.