Toll-like receptors (TLRs) detect infections by highly conserved components of pathogens that are either not present in our own cells or are normally sequestered in cellular compartments that are inaccessible to the TLRs. Most TLRs are expressed on the cell surface, where they have been shown to detect pathogen-expressed molecules such as lipopolysaccharides and lipopeptides. A subset of TLRs, including TLR3, TLR7, TLR8, and TLR9, are expressed intracellularly within one or more endosomal compartments and detect nucleic acids. Because pathogen and host nucleic acids have very similar structures, these endosomal TLRs may face an extra challenge to induce anti-pathogen immune responses while avoiding the induction of autoimmune diseases. With the rapid growth in understanding of the biology of the TLRs has come an increasing awareness of their effects on autoimmunity, several aspects of which are the focus of this review. First, recent studies have revealed an inappropriate activation of TLR7, TLR8, and TLR9 in systemic lupus erythematosus and several other autoimmune diseases. Secondly, the potential for therapeutic development of TLR antagonists is considered. Finally, with the rapid progress in the development of therapeutic agonists for the TLRs, there is accompanying attention to the theoretical possibility that such therapy may induce autoimmunity or autoimmune diseases.