An increasing body of data supports the role of the innate immune system in the pathogenesis of rheumatoid arthritis (RA). Toll-like receptors (TLRs) are expressed by cells within the RA joint and various endogenous TLR ligands are present within the inflamed joints of patients with RA. Further, various animal models suggest that TLR signaling is important in the pathogenesis of disease. Overall, the data suggest that activation by endogenous TLR ligands may contribute to the persistent expression of proinflammatory cytokines by macrophages and the joint damage to cartilage and bone that occurs in RA. The data support a potential role for suppression of TLR signaling as a novel therapeutic approach in patients with RA.