The melanocyte can give rise to a variety of both benign and malignant lesions that differ in their clinical and histopathological appearance. It is likely that genetic changes underlie this phenotypic diversity. Comparative genomic hybridization (CGH) is a genome-wide scanning technique that permits the measurement of copy number aberrations in archival tumors. Using CGH, we have demonstrated significant differences in the frequency of chromosomal aberrations in primary cutaneous melanomas and Spitz nevi. Whereas the majority of melanomas have aberrations frequently involving chromosomes 9, 10, 7, and 6, most Spitz nevi do not show aberrations. However, a small subset of Spitz nevi show an isolated gain of the short arm of chromosome 11p. As this aberration has not been observed in melanomas, the measurement of chromosomal aberrations should be further evaluated as a diagnostic tool for ambiguous melanocytic tumors.