The possible role of infections in driving autoimmune disease (AD) has long been debated. Many theories have emerged including release of hidden antigens, epitope spread, anti-idiotypes, molecular mimicry, the adjuvant effect, antigenic complementarity, or simply that AD could be a direct consequence of activation or subversion of the immune response by microbes. A number of issues are not adequately addressed by current theories, including why animal models of AD require adjuvants containing microbial peptides in addition to self tissue to induce disease, and why ADs occur more often in one sex than the other. Reviews published in the past 3 years have focused on the role of the innate immune response in driving AD and the possible role of persistent infections in altering immune responses. Overall, recent evidence suggests that microbes activating specific innate immune responses are critical, while antigenic cross-reactivity may perpetuate immune responses leading to chronic autoinflammatory disease.