It is now well-accepted that autoimmune diseases develop as a result of interactions between a complex genetic basis and environmental triggers. Autoreactive B cells play a major role in many autoimmune diseases, by secreting autoantibodies or cytokines and/or presenting auto-antigens to T cells. Studies performed with human patients and murine models have accumulated evidence that B-cell autoreactivity, or its manifestation as the presence of autoantibodies, are also supported by multiple genetic determinants. These studies will be summarized in this review and presented in a critical perspective of the approaches used to obtain these results, and their significance for our understanding of B-cell tolerance.