The complement system is comprised of a number of serum and membrane-bound proteins that play an important role in the elimination of foreign microorganisms while protecting the host organism from complement-related damage. Complement has also been shown to participate in the generation of normal humoral immune responses to foreign antigens. Recent studies suggest that the functions of complement may be extended to include the maintenance of B cell tolerance. Complement receptor 2 (CR2/CD21) has been implicated in lupus susceptibility in both humans and animal models of disease. Located primarily on B cells and follicular dendritic cells, CR2 binds C3 degradation products that have become covalently bound to antigen or immune complexes in the process of complement activation. The mechanism by which CR2 might regulate B cell reactivity to autoantigens has not been elucidated, but may involve direct effects on B cell tolerance or indirect effects on T cell tolerance.