Extracellular matrix (ECM) remodeling is strongly favored by the conditions occurring in the inflammatory microenvironment and can lead to pathogenic reactions directed toward the ECM itself Several reports have described autoimmune responses to ECM molecules in patients with inflammatory diseases whose pathogenesis is not primarily related to ECM autoimmunity. This review will focus on the molecular interplay that governs ECM remodeling during tissue inflammation and will discuss how chronic inflammation can act as a driving force for the induction of autoimmune responses to ECM components as well as how the elicited autoimmunity can sustain local or induce distant tissue damage.