Toll-like receptors (TLRs) have attracted increased attention in recent years, not only for their role in sensing conserved microbial components, but also in the realm of autoimmunity. Although TLRs are most widely known for their capacity to detect conserved motifs of infectious agents, mounting evidence indicates that these innate receptors also promote autoimmune conditions by causing uncontrolled autoinflammation as a result of chronic recognition of self. In response to the need for modern approaches to treatment of autoimmune diseases, several groups have begun investigating ways to target TLRs as new therapeutic options for autoimmune conditions. Here we discuss recent data describing advances in TLRs as therapeutic targets for treatment of autoimmune diseases, with a focus on systemic lupus erythematosus.