Spontaneous melanoma in hybrids of Xiphophorus is caused by overexpression of the receptor tyrosine kinase gene Xmrk. In rare cases melanoma also occurs in non-hybrid fish from natural habitats where the trigger is unknown. In these tumors Xmrk is overexpressed too, pointing to a similar molecular mechanism underlying neoplastic transformation. After carcinogen treatment a variety of tumor of other histiotypes are induced. Tumor genes other than Xmrk seem to cause these neoplasias. Genetic alterations have been detected in a recently isolated mutant, and immunomodulators, and androgens can cause regression of hybrid melanoma. The variety of etiologies and the multiplicity of exogenous factors and agents that induce cancer or modify the neoplastic phenotype allow the study in Xiphophorus of many of the problems of tumorigenesis found in vivo.