Systemic autoimmune diseases are the result of complex interactions among T cells, B cells, and target tissues. Because of these interactions, it has been difficult to distinguish the contributions of various cell types to both the initiation of the autoimmune response and the resultant specific pathologic lesions. It has also been difficult to isolate the early events in what is undoubtedly a cascade of amplifying events, in part because of the interdependence of B and T cell activation. To better address these issues, various genetic murine models of lupus, a prototypical human systemic autoimmune disease, have been developed. Disease in these mice has been carefully described. Although no murine model exactly resembles human SLE, they have been very useful in identifying the mechanisms of pathogenesis and the roles of important cell types. For example, transfer of antibodies (Abs) and cells has allowed identification and characterization of pathogenic autoantibodies and cell^.^-^ Treatment of mice with anti-Thy16 or anti-CD4 Abs7 has established important roles for CD4+ T cells in auto-Ab production and disease. Although such studies have been informative, they are limited. In particular, it is not possible to reconstitute Ab-suppressed animals in order to prove the role of the cells in question and better define subsets of important cells. By crossing these murine lupus models with knockout mutations that affect T cells or B cells, a more precise elucidation may be possible of the role of T and B cell subsets and their interactions in autoimmune dysfunction. Because specific cells or molecules are eliminated in such mice without exogenous intervention, they can also serve as recipients in reconstitution experiments, which greatly extend the power of the analysis. In this manuscript, we will summarize our own work using this approach on the role of B cells in nephritis and vasculitis and will present some new data on the role of B cells in spontaneous T cell activation.