Altered dynamics of cartilage and bone matrix in joint diseases results in increased release of macromolecules into synovial fluid (SF). Such macromolecules are increasingly explored as potential markers of damage and severity. This report focuses on the possibilities of using quantification of tissue specific markers for grading the tissue lesion at the molecular level in arthritis. The theoretical and experimental rationale for such an approach is supported by the results in clinical studies. These studies indicate that simultaneous analysis of multiple cartilage and bone markers in the same SF or serum sample could be useful for defining degree of tissue involvement in rheumatoid arthritis and, possibly, in osteoarthritis.