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/D^b 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 Sxr^b 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 Sxr^b 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.