Toll-like receptors (TLRs) recognize molecular patterns relating to a variety of microbial infections. Stimulation through TLRs leads to activation of antigen-presenting cells, production of inflammatory cytokines creating inflammation, and production of type 1 interferons (IFNs) that include IFN-α and -β, and exerts direct effects on regulatory cells. These effects can direct the immune response, dealing with the immediate problems of infection and activating more specific responses of the adaptive immune system. However, it has recently been recognized that these receptors may recognize endogenous ligands that include DNA, RNA, and proteins that arise from cellular stress. This may have an effect on autoimmune responses in a number of ways, both activating and inhibitory. The means by which infection or endogenous stimuli through TLRs may influence autoimmunity will be discussed.