The development of rheumatoid arthritis (RA) occurs as a result of interactions between genes and environment. The most well established association with both susceptibility and severity of disease is variations in the major histocompatibility complex (MHC) class II genes. This fact constitutes evidence in favor of a contribution from specific MHC class II restricted adaptive immunity to the pathogenesis of RA. However, considerable difficulties have been encountered in identifying reactivities within the adaptive immune system that are responsible for the development of chronic arthritis in humans. In this article, the authors suggest a hypothesis for arthritis development based on their, as well as others', research. In patients with certain genetic contexts, RA can be initiated by activation of the innate immune system alone. In other patients, the adaptive immune system may be needed for the induction of disease. Additionally, the authors believe that a perpetuation to a severe chronic arthritis occurs only when both the adaptive and the innate immune systems have been recruited.