Malignant melanomas can be divided into two major subtypes, involving either the skin or eye melanomas. Both tumor forms exhibit highly complex karyotypes with nonrandom recurrent chromosomal imbalances. Loss of chromosome 3, the short arm of chromosome 1, and gain of 8q have been suggested to be associated with eye melanomas, whereas gain of 6p and loss of 6q have been more often seen in skin melanomas. Imbalances implicated in tumor progression include among others, −10 and +7. In spite of the abundance of cytogenetic information, with more than 300 published karyotypes, very little is known about the mode of karyotypic evolution or of the presence of possible cytogenetic pathways. In our investigation, we have used 362 melanoma karyotypes, including both the skin and eye subtypes, to identify the most frequently occurring imbalances. Tumor cases were then classified with respect to the presence or absence of these imbalances and statistically analyzed in order to assess the order of appearance of chromosomal imbalances, the presence of karyotypic pathways, as well as possible cytogenetic subtypes. We show that the melanomas develop through one mode of karyotypic evolution, common to both low and high complexity karyotypes, and we establish the temporal order by which the different imbalances occur. By applying several statistical methods, we show that at least two cytogenetic pathways of clonal evolution exist in malignant melanomas, one initiated with −3 and one with +6p, and that these pathways operate in both skin and eye melanomas. © 2003 Wiley-Liss, Inc.