Antibodies are involved in the pathogenesis of many autoimmune diseases. Although the mechanisms underlying the antibody response to infection or vaccination are reasonably well understood, we still have a poor understanding of the nature of autoimmune antibody responses. The most well studied are the anti-nuclear antibody responses characteristic of systemic lupus erythematosus and studies over the past decade or so have demonstrated a critical role for signaling by TLR7 and/or TLR9 in B cells to promote these responses. These Toll-like receptors (TLRs) can promote T-cell-independent extrafollicular antibody responses with a heavy-chain class switch and a low degree of somatic mutation, but they can also strongly boost the germinal center response that gives rise to high-affinity antibodies and long-lived plasma cells. TLRs have been shown to enhance affinity maturation in germinal center responses to produce high-affinity neutralizing antibodies in several virus infection models of mice. Although more data are needed, it appears that anti-nuclear antibodies in mouse models of lupus and in lupus patients can be generated by either pathway, provided there are genetic susceptibility alleles that compromise B-cell tolerance at one or another stage. Limited data in other autoimmune diseases suggest that the germinal center response may be the predominant pathway leading to autoantibodies in those diseases. A better understanding of the mechanisms of autoantibody production may ultimately be helpful in the development of targeted therapeutics for lupus or other autoimmune diseases.