Damage-associated molecular patterns (DAMPs) are endogenous molecules released during cellular damage or stress, which can activate the innate immune system. DAMPs include nucleic acids, proteins, ions, glycans, and metabolites. Under normal conditions, these molecules are not immunogenic, but upon damage, they become DAMPs that can be sensed by innate immune receptors, triggering inflammatory responses. This review summarizes the conversion of homeostatic molecules into DAMPs, their diverse nature, classification, cellular origin, and sensing mechanisms, as well as their roles in inflammation and related diseases. It also discusses clinical strategies targeting DAMP-sensing receptors to treat DAMP-associated diseases. DAMPs are recognized by pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs), C-type lectin receptors (CLRs), RIG-I-like receptors (RLRs), NOD-like receptors (NLRs), and DNA sensors. TLRs recognize DAMPs like HMGB1, HSPs, histones, and decorin, leading to the activation of inflammatory signaling pathways. CLRs, such as Dectin-1 and MINCLE, recognize glycans and endogenous molecules, promoting immune cell activation. RIG-I and MDA5 recognize self-RNA, leading to IFN-I production. DNA sensors like cGAS and AIM2 detect self-DNA, activating inflammasomes and promoting inflammation. DAMPs are generated through various cellular processes, including cell death (necrosis, pyroptosis, ferroptosis), organelle damage, and metabolic dysregulation. DAMPs such as HMGB1, mtDNA, and oxidized lipids can activate the NLRP3 inflammasome, leading to inflammation and disease. The sensing of DAMPs by receptors like TLRs, CLRs, and NLRP3 is crucial for immune responses and tissue repair. Targeting DAMP-sensing receptors offers potential therapeutic strategies for inflammatory diseases.Damage-associated molecular patterns (DAMPs) are endogenous molecules released during cellular damage or stress, which can activate the innate immune system. DAMPs include nucleic acids, proteins, ions, glycans, and metabolites. Under normal conditions, these molecules are not immunogenic, but upon damage, they become DAMPs that can be sensed by innate immune receptors, triggering inflammatory responses. This review summarizes the conversion of homeostatic molecules into DAMPs, their diverse nature, classification, cellular origin, and sensing mechanisms, as well as their roles in inflammation and related diseases. It also discusses clinical strategies targeting DAMP-sensing receptors to treat DAMP-associated diseases. DAMPs are recognized by pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs), C-type lectin receptors (CLRs), RIG-I-like receptors (RLRs), NOD-like receptors (NLRs), and DNA sensors. TLRs recognize DAMPs like HMGB1, HSPs, histones, and decorin, leading to the activation of inflammatory signaling pathways. CLRs, such as Dectin-1 and MINCLE, recognize glycans and endogenous molecules, promoting immune cell activation. RIG-I and MDA5 recognize self-RNA, leading to IFN-I production. DNA sensors like cGAS and AIM2 detect self-DNA, activating inflammasomes and promoting inflammation. DAMPs are generated through various cellular processes, including cell death (necrosis, pyroptosis, ferroptosis), organelle damage, and metabolic dysregulation. DAMPs such as HMGB1, mtDNA, and oxidized lipids can activate the NLRP3 inflammasome, leading to inflammation and disease. The sensing of DAMPs by receptors like TLRs, CLRs, and NLRP3 is crucial for immune responses and tissue repair. Targeting DAMP-sensing receptors offers potential therapeutic strategies for inflammatory diseases.