Toll-like receptors (TLRs) are a category of receptors that recognize and activate their signaling pathways to defend against the pathogen factors. However, an alteration in the proper activation might occurr, resulting in the production of proinflammatory cytokines. This improper activation is the beginning of an autoimmune disease. The inhibition of the implicated receptors or their pathways may prevent the induction of autoimmunity. This paper describes in detail new therapeutic opportunities based on the alteration of the TLR activation for rheumatoid arthritis and systemic lupus erythematosus.