Members of the tumor necrosis factor (TNF) superfamily play important roles in cell proliferation and death during immune regulation. Most members are synthesized as type II transmembrane proteins; the carboxy terminal extracellular domain can be cleaved from the cell membrane to form soluble active cytokines that bind to appropriate members of the TNF receptor family. Here, we describe the biological significance of recently discovered members of the TNF superfamily (TALL-1 and APRIL) and their receptors (TACI and BCMA) in the pathophysiology of human diseases.