Extensive studies in lupus-prone mice strongly suggest that mAbs to CD4 may be effective in SLE. By virtue of their selectivity for distinct cells within the immune system, anti-CD4 mAbs may be both more potent and less toxic than current therapies for SLE. In addition, their potential to block the host immune response to therapy may provide a critical advantage for anti-CD4 compared to other forms of mAb therapy. The problem of generalized immune suppression remains a significant obstacle to the use of anti-CD4 in humans, but it may be minimized by the use of mAb fragments or mAb isotypes that can reversibly inhibit immune function without depleting CD4+ T cells.