Osteoarthritis (OA) is associated with a loss of the normal balance between synthesis and degradation of the macromolecules that provide articular cartilage with its biomechanical and functional properties. The destruction of joint cartilage involves the degradation of matrix molecules which are released as fragments to joint fluid, blood, and urine, where they may be detected, for example, by immunoassay. It has been suggested that such molecular markers of cartilage matrix metabolism could be used as markers to determine diagnosis, prognosis, and severity, to predict response to therapy and monitor response to therapy, and to identify disease mechanisms on the molecular level. Since markers reflect ongoing dynamic changes in joints, they are perhaps most likely to serve as measures of prognosis and measures of response to treatment. Some markers may serve multiple functions. To function as adequate tests, they should meet a set of standards. It is only when markers have met such criteria that they will be accepted in the research and clinical community and will become widely used.