Genetic studies of familial human cutaneous malignant melanoma have failed to support a single mode of inheritance. To eliminate the complexities of genetic heterogeneity, we have turned to appropriate animal models to gain insights into possible genetic mechanisms that may be applicable to the human. Cutaneous malignant melanoma of Sinclair miniature swine is an inherited malignancy with many of the histopathological characteristics of human melanoma. The actual mode of inheritance of the melanoma has not been determined. Recently, we initiated experiments to characterize the swine major histocompatibility complex in melanoma- and nonmelanoma-bearing animals. These experiments led to the discovery of two loci that are involved in the expression of exophytic melanomas. The first locus lies within the swine major histocompatibility complex where one particular haplotype produces a phenotype in which the effects of a second locus are fully penetrant. The second locus segregates independently of the major histocompatibility complex. The melanoma-producing allele at this second locus is inherited in the heterozygous state and requires a somatic mutation of the normal allele to initiate tumor development.