The nature of Spitz nevi is poorly understood, and their distinction from malignant melanoma can be difficult. Although there is general agreement on the diagnostic criteria, experts continue to have some differences, and controversial cases are not rare. A major obstacle to progress in this area is the lack of basic knowledge about melanocyte differentiation in Spitz nevi, as compared with ordinary nevi and malignant melanomas. Based on the hypothesis that normal melanocytes may have a differentiation pathway with discrete stages, it is suggested that the features of Spitz nevi may reflect homeostatic mechanisms governing maturation in the melanocyte differentiation pathway, whereas those of malignant melanomas may reflect carcinogen-induced aberrations. This perspective may be helpful in the continuing effort to develop optimal criteria for the differential diagnosis of Spitz nevi from malignant melanomas.