The TNF family of cytokines now contains nearly 20 members whose activities impact cell growth, differentiation, death, and survival in an extraordinary variety of physiological systems. It comes as little surprise that this important family of proteins has also been implicated in the pathology of many diseases, and is therefore the target of intense drug development efforts. Within the mammalian TNF family is a related group of proteins that includes APRIL, BAFF, TWEAK, and EDA which share sequence and structural homology. They are active on diverse cell types, including fibroblasts, B cells, endothelial cells, and epithelial cells. Such a diversity of activities may be the consequence of an ancient lineage, as a homologue of this family has recently been discovered in the fly. Here we will review the functions of this unique subfamily within the TNF family. Our attention will be focused primarily on APRIL and BAFF, however, we attempt to gain additional insight by considering the biology of TWEAK, EDA, and their relative from Drosophila, Eiger.