Understanding the pathogenesis of osteoarthritis (OA) provides invaluable information in the search of therapeutic targets for the development of disease-modifying OA drugs. Emerging results from investigations demonstrate that the pericellular matrix of chondrocytes plays important roles in protecting articular cartilages from being degraded. Thus, maintaining the structural integrity of the pericellular matrix may be an effective approach to prevent the development of osteoarthritic joints. In this review article, we discuss the consequences of lacking one or more components of the pericellular matrix, and biological effects of the destruction of the pericellular matrix in the development of OA. We believe that more attention should be directed towards the pericellular matrix for the identification of novel biomarkers and therapeutic targets for the prevention and treatment of OA.