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The long accepted model for tumor necrosis factor receptor (TNFR) signaling is that ligand binding causes receptors to trimerize, resulting in a stoichiometric change in their cytosolic domains. This model is incomplete in that it does not explain the importance of receptor self-interaction nor ligand/receptor network formation. Here, we introduce evidence for a novel TNFR activation mechanism based on network-induced conformational change in the receptor extracellular domain, which propagates through the transmembrane helices to bring about reorganization of the death domains. First, we use normal mode analysis to suggest a mechanism whereby ligand binding induces a conformational change in the TNFR1 extracellular domain which propagates through the membrane to the cytosolic domain. We validate this experimentally by measuring FRET using fluorophore tagged TNFR1 chimeras. We then characterize a scissors-like open-to-closed transition in the disulfide-linked death receptor 5 (DR5) transmembrane dimer that couples the extracellular and cytosolic conformational changes. Using quantitative confocal image analysis, we show that DR5 ligand/receptor networks form in both the absence and presence of membrane cholesterol, but in the absence of cholesterol fail to induce signaling. These networks differ in that they do not contain disulfide-linked DR5 dimers and we run molecular simulations to offer an explanation. We then show that oxidation strengthens the methionine-aromatic interaction, a highly stabilizing motif found in many proteins including TNFR1 and DR5, using biophysical, computational, and cell biological techniques. Lastly, we introduce mutations to the TNFR1 pre-ligand assembly domain to reduce its dimerization affinity and show that ligand binding does not directly depend on receptor self-association. Future work will determine the functional relevance of receptor dimerization and whether dimer dissociation can be exploited as a mechanism for TNFR1 signaling blockade. In summary, our results support a novel mechanism of TNFR activation that will guide the discovery and development of novel therapeutics for inflammatory disease and cancer.