The main purpose of this chapter is to describe and discuss the role of class I SLRPs biglycan, decorin, and asporin in the diseases of the matrix to reveal their essential regulatory roles. Class I SLPRs are expressed during the development of cartilage, bones, tendons, and ligaments, including collagen fibrillogenesis, cell differentiation, migration, inflammation, angiogenesis, and even cancer. Notably biglycan and decorin are considered as damage-associated molecular pattern recognition molecules influencing the regulation of signaling pathways that contribute to tissue pathogenesis; thus, this chapter highlights the functional significance and role of class I SLRPs.