Fishes of the genus Xiphophorus (platyfishes and swordtails) are small, internally fertilizing, livebearing, and derived from freshwater habitats in Mexico, Guatemala, Belize, and Honduras. Scientists have used these fishes in cancer research studies for more than 70 yr. The genus is presently composed of 22 species that are quite divergent in their external morphology. Most cancer studies using Xiphophorus use hybrids, which can be easily produced by artificial insemination. Phenotypic traits, such as macromelanophore pigment patterns, are often drastically altered as a result of lack of gene regulation within hybrid fishes. These fish can develop large exophytic melanomas as a result of upregulated expression of these pigment patterns. Because backcross hybrid fish are susceptible to the development of melanoma and other neoplasms, they can be subjected to potentially deleterious chemical and physical agents. It is thus possible to use gene mapping and cloning methodologies to identify and characterize oncogenes and tumor suppressors implicated in spontaneous or induced neoplasia. This article reviews the history of cancer research using Xiphophorus and recent developments regarding DNA repair capabilities, mapping, and cloning of candidate genes involved in neoplastic phenotypes. The particular genetic complexity of melanoma in these fishes is analyzed and reviewed.