The antigens that trigger the pathogenic immune response in rheumatoid arthritis remain unknown. Until recently it was assumed that joint-specific antigens were the targets of arthritogenic T lymphocytes and B lymphocytes in rheumatoid arthritis. Consequently, murine models of arthritis are induced by immunization with either joint-specific antigens such as type II collagen or microbial products such as streptococcal cell wall. In the K/BxN T-cell receptor transgenic mouse model, arthritis is caused by a systemic autoimmune response to the ubiquitously expressed glycolytic enzyme glucose-6-phosphate isomerase (G6PI). More recently it was shown that G6PI immunization induces severe symmetrical peripheral polyarthritis in genetically unaltered DBA/I or SJL mice [1, 2]. T cells are indispensable for both the induction and the effector phase of G6PI-induced arthritis. Arthritis is cured by depletion of CD4 cells. In contrast, antibodies and FcγR effector cells are necessary but not sufficient for G6PI-induced arthritis in genetically unaltered mice [1]. Both the induction and effector phase of arthritis induced by a systemic autoimmune response can be dissected and preventive and therapeutic strategies evaluated in this model.