Periodontitis is an inflammatory disease triggered by microbial biofilms that promote immune dysfunction and tissue destruction of tooth-supporting tissues. The search for soluble mediators that amplify inflammatory responses and matrix degradation in periodontal tissues has implicated extracellular vimentin (ECV) as a signaling ligand and damage-associated molecular pattern in the pathogenesis of periodontitis. Intracellular vimentin filaments are essential for the structural integrity of cells and the preservation of matrix homeostasis. These are important determinants of health in the periodontium and many other organs. But in inflamed tissues, intracellular vimentin filaments are disassembled. Vimentin is subsequently released from cells into the extracellular space in a soluble form where it drives immune signaling and tissue destruction. We discuss the role of ECV as a signaling molecule in several tissues. We apply these data to understand how in inflammatory diseases like periodontitis, ECV amplifies immune responses that contribute to disease progression. Arising from these data, we consider novel therapeutic opportunities for limiting tissue destruction by targeting ECV for treatment of inflammatory disorders like periodontitis.