The S-S bond is integral to the structure and function of diverse classes of natural products, peptides and proteins, drug molecules, and polymers. The utility of the S-S bond stems from its ability to break and reform in response to diverse stimuli including heat, 8 nucleophilic or basic catalysts, oxidants and reductants, electrochemical potentials, 13 light, 14 ball milling, pressure, or sonication. The dynamic nature of the S-S bond has been leveraged in many applications such as peptide and protein modification, drug delivery, combinatorial chemistry, and self-healing materials. Organic disulfides (R-S-S-R, where R = carbon) are the most widely explored linkages in these applications, and radical or ionic intermediates are commonly invoked in mechanistic descriptions of these S-S exchange reactions (Figure ). Uncatalyzed disulfide metathesis at room temperature, without the aforementioned energy inputs or chemical stimuli, is extremely rare. Organic trisulfides (R-S-S-S-R), while less widely studied than disulfides, are intriguing functional groups found in several natural products, anti-tumor compounds, and vulcanized rubber. Trisulfides have also found recent use as cathode materials for rechargeable batteries. Thermally induced S-S exchange reactions of trisulfides have been investigated for more than 50 years, with foundational insights provided by Coran 30 and Tobolksy. These studies established the ability of organic trisulfides to undergo S-S exchange in benzene, nitrobenzene or solvent-free conditions at temperatures ranging from 80 to 150 ºC. Under such conditions, the S-S exchange required hours or days to reach equilibrium (Figure ). Evidence for radical intermediates and the production of di-, tri-and tetrasulfides was provided in these thermally-induced S-S exchange reactions. Recently, we encountered an unusually fast trisulfide metathesis reaction while investigating the processing and recycling of polymers containing polysulfide crosslinks. Specifically, we discovered that simple linear trisulfides underwent rapid exchange at room temperature in either pyridine or amide-containing solvents such as dimethylformamide (DMF), dimethylacetamide (DMA), and Nmethyl-2-pyrrolidone (NMP). In these reactions, the exchange reaction was complete within minutes at room temperature and only trisulfides were formed: no disulfides or tetrasulfides were observed. Mechanistically, tentative hypotheses were proposed that rationalized pyridine as a nucleophilic catalyst that provoked an ionic S-S exchange reaction; 32 DMF, DMA, and NMP were proposed to coordinate to sulfur, weaken the trisulfide S-S bond, and accelerate homolytic cleavage for S-S exchange via radical intermediates. In this study, we reveal that neither of these previously reported mechanisms fully account for these trisulfide exchange reactions. Instead, a novel trisulfide metathesis mechanism is proposed that features neither ionic nor radical intermediates, and accounts for the exclusive formation of trisulfide exchange products. Detailed examination of solvent effects, substrate scope, mechanistic probes, reaction inhibitors, and computational insights revealed a new reaction manifold for S-S exchange that is unique to organic trisulfides. This understanding enabled wide-ranging applications of this chemistry in dynamic combinatorial library synthesis, direct modification of complex natural products, and S-S metathesis polymerization and depolymerization as a platform for recyclable plastics (Figure ).