Toll-like receptor (TLR) activation by pathogens can induce the activation of diverse cell populations of the immune system and, therefore, can initiate or augment protective T-helper 1 immune responses. However, on a susceptible genetic background, TLR stimulation can also induce autoimmunity. The relative contribution of either microbe-derived or endogenous antigens, such as single-stranded RNA and unmethylated DNA, to TLR stimulation and the development of specific autoimmune diseases are still debated. Here, we review the different possibilities. Furthermore, tolerance induction by TLRs, which originally had been postulated to be protective by limiting excessive inflammation and, thus, preventing septic shock, has come into focus as a mechanism to control autoimmunity by inhibiting dendritic-cell maturation. In some murine models of systemic lupus erythematosus, TLR9 deficiency results in a shift from anti-nucleosome to TLR7-dependent anti-ribonucleoprotein IgG2a and IgG2b autoantibodies, and enhanced disease progression and mortality. Thus, not only can TLR signalling induce autoimmunity, but TLR(9) stimulation might also regulate tolerance.