Abstract Molecular genetic analysis of the murine MHC reveals that the class I gene family is far larger than expected from immunogenetic analysis of class I polypeptides. Of approximately 30 class I genes present in mouse DNA most are located telomeric to the H-2 regions in the adjacent Qa and Tla regions. Although it is not yet known how many class I genes from the Qa and Tla regions are expressed to produce class I polypeptides, evidence is accumulating that at least some of these genes encode polypeptides whose structure, and presumably function, is very different from the H-2K, D and L class I polypeptides. Here, Andrew Mellor reviews the structural data which reveals the unexpeted complexity of the class I gene family, particularly in the Qa and Tla regions. He discusses how molecular cloning and analysis of these genes are providing evidence that class I genes in these regions encode polypeptides which are highly homologous to the classical H-2 antigens but which are structurally and functionally quite distinct from them.