This chapter describes the proposition of class II SLRPs fibromodulin, lumican, osteoadherin, proline/arginine leucine-rich repeat protein (PRELP), and keratocan in matrix homeostasis and catabolism. So far, there are only a few published literature that collectively analyses the mechanisms, class II SLRP molecules undergo during various types of pathological changes occurring in the matrix including their potential to act as damage-associated molecular pattern recognition molecules (DAMPs); however, there are also many independent studies assessing the significance of lumican and fibromodulin in tumor formation and in diseases of cartilage, bone, muscle, and skin indicating their potential to act as biomarkers of disease. Thus, this chapter explores the spatiotemporal expression analysis of class II SLRPs and provides significant clues toward understanding the regulatory roles these molecules play in development, diseases, as well as in the maintenance of tissue structure in adult life, thus this chapter aims to facilitate an in-depth understanding on the importance of class II SLRP molecules in the extracellular matrix.