Although the life span of patients with systemic lupus erythematosus (SLE) has improved considerably over the last several decades, the toxicities of chronic immunosuppressive therapy are major causes of morbidity and mortality. Safer and more effective therapies for SLE are clearly needed. SLE is characterized by excessive activation of both B and T lymphocytes. Activation of these cells requires both antigen engagement and co-stimulatory signals from interacting lymphocytes (Carreno, B.M. M. Collins, 2002, Annu. Rev. Immunol. 20: 29-53; Grewal, I.S. R.A. Flavell, 1998, Annu. Rev. Immunol. 16: 111-135). Thus, blockade of co-stimulatory signals offers a new therapeutic approach to SLE. Our short-term goal has been to understand the effect of co-stimulatory blocking reagents on the development, selection, and activation of pathogenic anti-dsDNA antibody producing B cells in mice genetically pre-determined to develop SLE and showing signs of either early or advanced disease activity. Our long-term goal is to use the knowledge we gain to design therapeutic regimens for humans that avoid the complications of long-term immunosuppression. As new co-stimulatory molecules are discovered, studying their mechanism of action in animal models and their clinical utility in human autoimmune disease should lead both to a new understanding of disease pathogenesis and also to safer and more effective therapies.