The genetic influence on rheumatoid arthritis (RA) is very complex with both polygenicity and heterogeneity and most likely with variable penetrance due to a strong influence by environmental factors. To make it possible to analyse which genes are of importance for controlling the disease and to further understand the basic pathogenesis, we use animal models in mice and rats. With gene segregation F2 experiments we have identified the major gene regions controlling the collagen induced arthritis in the mouse and pristane induced arthritis in the rat. In the rat we have found that different genes are controlling different phases of the disease, such as arthritis onset, erosions of the joints and the chronic development of arthritis. The most important gene region in both rats and mice is located in the major histocompatibility complex (MHC). In the mouse we have proved that the gene in the MHC region, which is responsible for the effect, is a class II gene called Aq. Interestingly, the protein encoded by this gene is structurally very similar to the RA-associated DR4B1*0401/DRA gene product, and mice expressing the human molecule are susceptible to collagen-induced arthritis. The function of these molecules is to bind peptides derived from different infectious agents and then present them to T lymphocytes. Both Aq and DR4 molecules bind peptides derived from position 260-273 in type II collagen. Studies using this structural knowledge show that 1) T cells recognize predominantly carbohydrate modifications of the peptide, and 2) the T cells are partially tolerized but can nevertheless participate in the induction of arthritis. In conclusion, these studies show that animal models are highly useful for specific analysis of the pathogenesis of RA by identifying genes and humanizing mouse strain.