Damage-associated molecular patterns (DAMPs) are intracellular molecules released under cellular stress or recurring tissue injury, which serve as endogenous ligands for toll-like receptors (TLRs). Such DAMPs are either actively secreted by immune cells or passively released into the extracellular environment from damaged cells or generated as alternatively spliced mRNA variants of extracellular matrix (ECM) glycoproteins. When recognized by pattern recognition receptors (PRRs) such as TLRs, DAMPs trigger innate immune responses. Currently, the best-characterized PRRs include, in addition to TLRs, nucleotide-binding oligomerization domain-like receptors, RIG-I-like RNA helicases, C-type lectin receptors, and many more. Systemic sclerosis (SSc) is a chronic autoimmune condition characterized by inflammation and progressive fibrosis in multiple organs. Using an unbiased survey for SSc-associated DAMPs, we have identified the ECM glycoproteins fibronectin-containing extra domain A and tenascin C as the most highly upregulated in SSc skin and lung biopsies. These DAMPs activate TLR4 on resident stromal cells to elicit profibrotic responses and sustained myofibroblasts activation resulting in progressive fibrosis. This review summarizes the current understanding of the complex functional roles of DAMPs in the progression and failure of resolution of fibrosis in general, with a particular focus on SSc, and considers viable therapeutic approaches targeting DAMPs.