Small leucine-rich proteoglycan (SLRP) molecules are involved in the regulation of sterile inflammatory disorder as recent and past research spanning over two decades provide ample evidence on the role of various SLRPs and its fragments in tissue catabolism. As described in Chap. 1 , SLRPs are ubiquitous, non-collagenous, secreted proteins with a core size of approximately 36–60 kDa presenting a characteristic leucine-rich repeat flanked with or without glycosylated side chains. The SLRP protein core undergoes post-translational modification during tissue stress, injury and pathological diseases breaking down the SLRP molecules in smaller fragments which are released into the extracellular matrix; these proteolytic fragments are able to interact with cellular receptors, cytokines, chemokines, growth factors, enzymes and many other matrix components. SLRPs can thus exist in a matrix-bound, sequestered or even a soluble form which reflects as the stage of the diseased matrix. Therefore, the main aim of this chapter is to elucidate in detail about the SLRP types that are most active in cancer and cartilage, renal, skin and other common tissue diseases compromising the extracellular matrix integrity. This chapter also explains about the dual role of SLRPs as an inhibitor and an activator of matrix metalloproteases.