Both genetic predispositions and environmental factors contribute to the development of autoimmunity. Toll-like receptors (TLR) are a family of pattern recognition receptors (PRRs), and their stimulus by pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) is an important prerequisite for the induction of various autoimmune diseases. However, activation of specific TLRs can not only induce but also inhibit autoimmune diseases in certain mouse models. The contribution of individual TLRs to the induction of autoimmunity or tolerance involves hematopoietic as well as nonhematopoietic cells expressing combinations of different TLRs. The intercellular and intracellular orchestration of signals from different TLRs, other PRRs, and membrane-standing receptors dictates activating or inhibitory responses. Here, we summarize TLR-dependent tolerance mechanisms in B cells and intestinal epithelial cells and TLR-mediated activation mechanisms leading to the induction of Th17 T cell differentiation in different autoimmune diseases and in inflammatory bowel diseases. Understanding the opposing mechanisms of TLRs for the induction and suppression of autoimmune processes in specific diseases will help to develop novel therapies to treat autoimmunity.