HLA class I transgenic mice are a powerful research tool which have been used as models for human immune responses. This review describes the generation of the different HLA class I transgenic mice, the techniques used to improve expression of the transgene and use of the transgene product in immune responses. It also illustrates how HLA class I transgenic mice have provided insights into the nature of the allogeneic and xenogeneic response, the generation of CTL responses, the development of autoimmune diseases, and their use for the generation of anti-HLA class I antibodies. Despite these advances, the use of available HLA class I transgenic mice as models for human disease and immune responses has been limited. The development of new transgenic strains incorporating multiple human transgenes may allow the potential of HLA class I transgenic mice to be realised.