Type 1 Neurofibromatosis (NF1) is characterized by the formation of neurofibromas, benign tumors composed mainly of Schwann cells, which can turn malignant to form neurofibrosarcomas. Neurofibromin, the protein product of the Nf1 gene, is believed to act as a tumor suppressor, accelerating the conversion of the oncogene Ras to its inactive form. The absence of neurofibromin could therefore lead to higher Ras activity in Schwann cells, resulting in uncontrolled growth through a cascade of events not yet elucidated. We describe the abnormal expression of high levels of the Kit tyrosine kinase receptor in both NF1-derived Schwann cell lines and tissue, as compared to primary Schwann cells or schwannoma-derived cells. High levels of Kit expression in the neurofibrosarcoma-derived Schwann cells correlate with a decrease in neurofibromin expression. Using inhibitors of tyrosine kinase receptors, we found that proliferation of the neurofibrosarcoma-derived cells is dependent upon activation of a subclass of tyrosine-kinase receptors. The proliferation of these cells is not dependent upon an autocrine loop involving typical Schwann cell mitogens. Finally, the proliferation of the neurofibrosarcoma-derived Schwann cells can be increased by stimulation with Kit ligand. These data implicate Kit as one of the components leading to the Schwann cell hyperplasia observed in NF1.