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Members of the tumor necrosis factor (TNF) superfamily of cytokines are noncovalently linked trimers that play important roles in regulating the immune system and have emerged as successful therapeutic targets in various rheumatic and autoimmune conditions. Traditionally, antibodies to cytokines or receptor-Fc fusion proteins have been used to block signaling by TNF family cytokines. In this issue of Science Signaling, Warren et al. have taken a new approach to blocking the action of the TNF superfamily member RANKL [receptor activator of nuclear factor κB (RANK) ligand], which plays an important role in regulating bone turnover through stimulation of its receptor RANK on osteoclasts. Beginning with a single-chain fusion protein of three RANKL subunits, the authors used directed mutagenesis to generate a trimer consisting of a nonreceptor binding subunit fused to two “super-agonist” subunits that have increased affinity for RANK. This molecule antagonized the osteoclastogenic activity of wild-type RANKL in vitro and in vivo, thus providing insights into RANK signaling and a paradigm for the development of other antagonists of TNF family cytokines.