The article reviews the role of damage-associated molecular patterns (DAMPs) in modulating Toll-like receptor (TLR) signaling and their implications in various inflammatory and autoimmune diseases. DAMPs, including intracellular molecules released by activated or necrotic cells and extracellular matrix (ECM) molecules upregulated upon injury, act as vital danger signals to alert the immune system to tissue damage. TLRs, key molecular links between tissue injury, infection, and inflammation, can be activated by both PAMPs and DAMPs. However, excessive inflammation, often associated with chronic diseases like rheumatoid arthritis (RA), cancer, and atherosclerosis, is linked to aberrant TLR activation by DAMPs. The authors discuss the distinct signaling cascades resulting from self-TLR activation, highlighting the differences between PAMP- and DAMP-induced inflammation. They also explore the involvement of endogenous TLR activators in disease and suggest that targeting DAMPs may offer therapeutic benefits without globally suppressing the immune system. Key findings include the identification of various endogenous TLR activators, such as heat shock proteins (HSPs), high mobility group box-1 protein (HMGB1), and ECM molecules, and their mechanisms of action. Additionally, they review studies demonstrating that high levels of DAMPs are associated with inflammatory diseases, and that inhibition of DAMP action can ameliorate disease progression in animal models. The article concludes by discussing potential therapeutic strategies, including blocking DAMP activation of TLRs, preventing DAMP accumulation, and manipulating co-receptors or accessory molecules essential for DAMP activation. It emphasizes the need for further research to understand the hierarchies among DAMPs and their role in inflammatory diseases, as well as the development of validated tools for measuring DAMP levels and their impact on disease.The article reviews the role of damage-associated molecular patterns (DAMPs) in modulating Toll-like receptor (TLR) signaling and their implications in various inflammatory and autoimmune diseases. DAMPs, including intracellular molecules released by activated or necrotic cells and extracellular matrix (ECM) molecules upregulated upon injury, act as vital danger signals to alert the immune system to tissue damage. TLRs, key molecular links between tissue injury, infection, and inflammation, can be activated by both PAMPs and DAMPs. However, excessive inflammation, often associated with chronic diseases like rheumatoid arthritis (RA), cancer, and atherosclerosis, is linked to aberrant TLR activation by DAMPs. The authors discuss the distinct signaling cascades resulting from self-TLR activation, highlighting the differences between PAMP- and DAMP-induced inflammation. They also explore the involvement of endogenous TLR activators in disease and suggest that targeting DAMPs may offer therapeutic benefits without globally suppressing the immune system. Key findings include the identification of various endogenous TLR activators, such as heat shock proteins (HSPs), high mobility group box-1 protein (HMGB1), and ECM molecules, and their mechanisms of action. Additionally, they review studies demonstrating that high levels of DAMPs are associated with inflammatory diseases, and that inhibition of DAMP action can ameliorate disease progression in animal models. The article concludes by discussing potential therapeutic strategies, including blocking DAMP activation of TLRs, preventing DAMP accumulation, and manipulating co-receptors or accessory molecules essential for DAMP activation. It emphasizes the need for further research to understand the hierarchies among DAMPs and their role in inflammatory diseases, as well as the development of validated tools for measuring DAMP levels and their impact on disease.