The tumor necrosis factor (TNF) family of cytokines and their receptors regulates many areas of metazoan biology. Specifically, this cytokine-receptor family plays crucial roles in regulating myriad aspects of immune development and functions. Disruption of ligand-receptor interaction or downstream signal transduction components in the TNF family often leads to pathological conditions. Historically, members of the TNF receptor family (TNFRs) were thought to exist as monomeric receptor chains prior to stimulation. Binding of the trimeric ligand then induces the trimerization of the receptors and activation of downstream signaling. However, recent evidence indicates that many TNFRs exist as pre-assembled oligomers on the cell surface. Pre-ligand assembly of TNFR oligomers is mediated by the pre-ligand assembly domain (PLAD), which resides within the membrane distal cysteine-rich domain of the receptors. Growing evidence indicates that PLAD-mediated receptor association regulates cellular responses to TNF-like cytokines, especially in cells of the immune system. Thus, targeting pre-ligand assembly may offer new possibilities for therapeutic intervention in different pathological conditions involving TNF-like cytokines.