An important hallmark of tissue remodeling is the dynamic turnover of extracellular matrix (ECM). ECM performs a variety of functions in tissue repair including scaffold formation, modulation of fluid dynamics, and regulating cell behavior. During non-infectious tissue injury ECM degradation products are generated that acquire signaling functions not attributable to the native precursor molecules. Hyaluronan (HA) is a non-sulfated glycosaminoglycan which is produced in great abundance following tissue injury. It exists both in a soluble form and as side chains on proteoglycans. HA has critical roles in development as well as a variety of biological processes including wound healing, tumor growth and metastasis, and inflammation. HA fragments share structural similarities with pathogens and following tissue injury can be recognized by innate immune receptors. Elucidating the protean roles of HA in tissue injury, inflammation, and repair will generate new insights into mechanisms of diseases characterized by chronic inflammation and tissue remodeling.