Fibronectin is a multifunctional glycoprotein present at low levels in the extracellular matrix of normal cartilage. In this tissue, as in others, it may be a component of a cell matrix adhesion complex together with cell-surface proteoglycans but also may play a role in the organization of the extracellular matrix. In osteoarthritis (OA), fibronectin content is markedly increased in the altered matrix because of an increased synthesis by the chondrocytes and accumulation in the extracellular matrix. At least part of the fibronectins synthesized in one degenerated cartilage is composed of isoforms more sensitive to proteolytic cleavage that are absent in normal cartilage. This increased content of fibronectin during osteoarthritic processes might entail several consequences related to the multiple functions of fibronectin and its generated fragments, namely a change in chondrocyte phenotype, a switch in synthesis of collagen type, an increased activity of locally secreted metalloproteases, and induction of self-proteolytic activities against gelatin and fibronectin. However, it is not yet clearly understood whether the early increased synthesis of fibronectin in OA acts as an “agent” in an attempt to repair cartilage by the chondrocytes or whether it acts as a deleterious “agent”.