Matrix organisation in a multicellular organism is essential for the maintenance of the inherent strength of structural proteins that exists between the collagens, elastins, proteoglycans, glycoproteins and the SLRPs. The intricate arrangement between the extracellular matrix molecules facilitates growth, motility and regulatory communications between the cells and its receptors. Small leucine-rich proteoglycans (SLRPs) are a distinctive type of protein present in the matrix that are characterised by a central core protein made of several leucine-rich repeats (LRRs) with covalently linked glycosaminoglycan (GAG) side chain. There are eighteen small leucine-rich proteoglycan protein molecules categorised in five distinct classes as the SLRP family, each of them exhibits a unique or common feature, and are  essential for sustaining the integrity of the molecular matrix. The pericellular localisation of SLRPs allows interaction between specific cell receptors with cytokines, enzymes, growth factors, collagens, aggregating and non-aggregating large proteoglycan molecules and other vital matrix components. The diverse biological role of SLRPs makes it a viable pharmacological target and biomarker in disease progression. Thus, the main aim of this chapter is to categorically introduce each member of the SLRP family and their role in various organs and tissue-related pathological diseases associated with cell-matrix dysregulation, including the consequences of joint overloading and age-related changes in cartilaginous and non-cartilaginous tissues.