MHC class II molecules function by selective binding of anti‐genic peptides, thereby both shaping the T‐cell receptor (TCR) repertoire in the thymus and influencing presentation of immunogenic peptides to CD4+ T cells in the periphery. The strong association between a number of human autoimmune diseases (type 1 diabetes, rheumatoid arthritis, and multiple sclerosis) and certain HLA‐DR/DQ alleles suggests that it may be possible to alter pathological autoimmune responses by deliberate introduction of autoantigenic peptides in a “tolerogenic” manner. Since there are likely to be differences in epitope selection and epitope spreading in different patients over time, this approach requires identification of all the immunogenic CD4^‐ T‐cell epitopes (dominant, subdominant, or cryptic) of an autoantigen which elicit T‐cell responses restricted to the HLA‐DR/DQ alleles predisposing to these autoimmune diseases. This paper describes a new approach for the identification of immunogenic peptide epitopes of human autoantigenic proteins using HLA‐DR and DQ transgenic mice. These mice are engineered to select a full TCR repertoire which can identify immunogenic peptide epitopes similar or identical to human subjects of the same HLA‐DR/DQ genotype. This experimental system also allows comparison of autoantigenic immune responses restricted to disease‐susceptible and disease‐resistant HLA‐DR/DQ alleles.