Autoimmunity is a serious health problem and understanding the maintenance and loss of tolerance to self-antigens are key issues in developing new therapeutic strategies to treat these diseases. Despite considerable progress toward understanding B cell tolerance and tolerance loss, much remains unknown, particularly regarding B cells specific for antigens targeted in disease. Our interest in systemic lupus erythematosus (SLE), a B cell-mediated autoimmune disease characterized by the production of autoantibodies to numerous nuclear antigens, is focused on understanding B cell tolerance and tolerance loss to the SLE-specific autoantigen Sm in mice and humans. Our work aims to provide the cellular and molecular underpinnings for the development of rational therapies to target autoreactive B cells in human SLE.