The proteins of the tumor necrosis factor (TNF) receptor superfamily are a group of cell-surface receptors critically involved in the maintenance of homeostasis of the immune system. By interacting with their corresponding ligands, these receptors either induce cell death or promote cell survival of immune cells. The number of recognized members of the TNF receptor and ligand superfamily has expanded substantially in the last several years. More important, the biologic function of this group of proteins has been closely associated with the regulation of the immune response and the pathogenesis of autoimmune disease. Thus, the direct targeting of these receptors by either inducing apoptosis or blocking survival of autoimmune T and B cells may be an important therapeutic strategy in the treatment of autoimmune disease. This review summarizes the recent progress in immunobiology of the TNF receptor superfamily and focuses on our studies of three critical family members - FasL/Fas, TNF-related apoptosis-inducing ligand (TRAIL)/TRAIL-Rs, and B lymphocyte stimulator (BLyS)/BLyS-Rs - to demonstrate the therapeutic potential of targeting these receptors for the treatment of autoimmune disease.