The genetic analysis of the domestic cat began with the assignment of 33 isozyme loci to 16 (of 19) chromosomal linkage groups using a panel of rodent x cat somatic cell hybrids. A domestic cat colony was established at the NIH Animal Center and linkage analysis of morphological loci and biochemical loci was initiated by computing log of the odds values of linked genes in pedigrees. Reciprocal skin grafts and allogenic lymphocyte immunizations were initiated and 15 standard antisera against the feline major histocompatibility complex (MHC) were derived. These sera have allowed the description and resolution of MHC haplotypes in four major cat colonies. The endogenous RD-114 retroviral family was studied in domestic cats by deriving molecular clones of endogenous RDV1 and performing restriction and chromosome mapping. The feline homologues of the proto-onc genes have been studied using molecular clones of v-onc and c-onc from man or mouse. To date, 10 oncogene loci have been genetically mapped and their role in feline tumorigenesis is under study. Eight enzyme loci that encode lysosomal enzymes known to be mutated in human inborn errors and in feline counterpart models have been assigned to specific feline chromosomes. Molecular cDNA clones of human lysosomal enzymes are being ligated to appropriate eukaryotic vectors for possible gene therapy in transgenic felids.