The patchy, mosaic nature of the hyperpigmentation defect in neurofibromatosis (NF) is shown to be compatible with a cell-cell interaction model involving at least 2, and perhaps 3 cell types. Two approaches to analysis of the cellular interaction model are outlined in detail: 1) Demonstration of the more or less random number, size, and distribution of café-au-lait spots (CLS); 2) Documentation of topographic features of hyperpigmentation and neurofibroma skin lesions with special significance, including: a) Localized, intense pruritus coincident with developing or numerous neurofibromas, responding to treatment with antihistamines or oral disodium cromoglycate (the mast cell is suggested as a mediator of the pruritus and perhaps of neurofibroma development); b) The high frequency of areolar neurofibromas in postpubertal NF females, suggesting a localized estrogenic effect on neurofibroma development; c) The recognition that the usual NF freckling (eg axillary) is essentially restricted to intertriginous zones and that they therefore probably have a different mechanism of origin than do CLS.