Transgenic and knockout mouse models have been invaluable for the elucidation of basic mechanisms in autoimmunity and have contributed new experimental models of human autoimmune diseases. Transgenic models of self tolerance have helped to change our view of this state from a process mediated purely by thymic deletion to a more complex process encompassing deletion, peripheral anergy, down-regulation of receptors and modulation by regulatory cells. Experiments in which the genes for the candidate target antigens in autoimmune disease are over-expressed or under-expressed have helped to clarify the targets of attack. Several examples of T cell receptor transgenic mice have been described in which T cells carry the receptor derived from a human or mouse autoimmune T cell clone. Such mice allow the characterization of T cell specificities contributing to disease and of the additional factors and checkpoints influencing disease development. In addition, the expression of disease associated HLA alleles in 'humanised' transgenic lines allows the mapping of HLA-restricted T cell epitopes and investigation of the mechanisms underlying these genetic associations. These approaches are leading to the generation of new disease models, offering hope for the design and testing of novel immunotherapeutic strategies.