Rheumatoid arthritis and other autoimmune diseases might be triggered by infectious agents. We have reviewed the evidence suggesting that mycoplasmas may play a role in the genesis of arthritis. Mycoplasmas are a common cause of spontaneous arthritis in many animal species. Numerous experimental models of mycoplasma-induced arthritis have been developed, some with mycoplasmas known to cause disease in humans. Mycoplasmas entertain complex relationships with the immune system of their hosts and frequently induce autoimmune events such as rheumatoid factor production. However, the potential role of mycoplasmas in human joint disease remains unknown. Mycoplasmas can be responsible for septic arthritis in patients with immune deficiencies, especially hypogammaglobulinemia. Whether mycoplasmas can incite or perpetuate inflammatory joint diseases such as rheumatoid arthritis remains controversial. Advances in molecular biology techniques for detecting infectious agents can be expected to settle this issue in the near future.