H-Y was originally discovered as a transplantation antigen. In vivo primary skin graft responses to H-Y are controlled by immune response (Ir) genes mapping to the MHC. In vitro T cell responses to H-Y are controlled by MHC class I and II Ir genes, which-respectively, restrict CD8 and CD4 T cells: These can be isolated as T cell clones in vitro. T cell receptor (TCR) transgenic mice have been made from the rearranged TCR genes of several of these, of which that specific for H-Y/Db is the best studied. Non-MHC Ir genes also contribute to the control of in vitro CTL responses to H-Y. The Hya/HYA gene(s) encoding H-Y antigen have been mapped using translocations, mutations, and deletions to Yq in humans and to the short arm of the Y chromosome in mice, where they lie in the deletion defined by the Sxrb mutation between Zfy-1 and Zfy-2. Hya/HYA has been separated from the testis-determining gene, Sry/SRY, in both humans and mice and in humans the azoospermia factor AZF has been separated from HYA. In mice transfection of cosmids and cDNAs mapping to the Sxrb deletion has identified two genes encoding H-Y peptide epitopes. Two such epitopes, H-Y/K(k) and H-Y/D(k), are encoded within different exons of Smcy and a third, H-Y/D(b), by a novel gene, Uty. Peptide elution approaches have isolated a human H-Y epitope, H-Y/HLA-B7, and identified it as a product of SMCY. Each of the Hya genes in mice is ubiquitously expressed but of unknown function. Their X chromosome homologues do not undergo X inactivation.