The small leucine-rich proteoglycans (SLRPs) are extensively localized extracellular matrix molecules that are dynamically synthesized, secreted, deposited, and degraded in vivo. SLRPs are pericellular in location that allows them to interact with other matrix molecules such as collagens, fibronectin, and fibrillin, as well as with various types of cellular receptors and signalling molecules. Nearly all classes of SLRPs regulate the vital process of collagen fibrillogenesis thereby contributing to the maintenance of tissue structure. During injury and inflammation in various tissue types, SLRPs degrade and lose their GAG side chain, and this process also affects aggrecan, a large proteoglycan molecules trapped within the fibrous network of collagen, ultimately altering the biochemical and mechanical structure of the matrix. SLRPs also act as a link molecule in the matrix, and thorough the combined action of increased mechanical loading, injury, and proteolytic activity of the matrix-degrading enzymes, SLRPs become fragmented into smaller sizes, which represents a common end stage of the pathological tissues. These cleaved SLRPs fragments can activate Toll-like receptors to initiate a sterile inflammatory reaction even in the absence of blood vessels, leading to upregulated expression of catabolic mediators and associated signaling pathways. Thus, small leucine-rich proteoglycans can act as damage-associated molecular patterns, as they cluster different types of receptors modulating altered signaling events that links the innate and adaptive immune response, and such changes in SLRPs expression leads to diverse biological consequences within the matrix. Therefore, the aim of this chapter is to summarize the multifactorial evidence behind the role of SLRPs as DAMPs.