The B lymphocyte stimulator (BLyS), also known as BAFF, THANK, TALL-1 and zTNF4, is the most recent addition to the tumor necrosis factor family (TNF) ligands and has a unique role in B cell immunity. Its requirement for the humoral immune response is evident in mice lacking BlyS, which exhibit profound deficiencies in peripheral B cell development and maturation. It regulates the antibody response, as shown in mice overexpressing BLyS, which develop autoimmune manifestations resulting from peripheral B cell expansion and differentiation. Attenuation of apoptosis appears to underlie BLyS action in B cells. However, elucidation of the mechanism of BLyS has proven to be more challenging, because BLyS binds three different TNF receptors (TACI/BCMA/BAFF-R) and shares overlapping functions with a related TNF ligand, APRIL. The unique role of BLyS in B cell development and differentiation and the pathogenesis of autoimmune diseases, systemic lupus erythematosus (SLE) in particular, makes the study of BLyS and its downstream targets attractive in the development of novel therapies.