Molecular markers or biomarkers have recently received growing attention in osteoarthritis (OA), due to their potential usefulness in early diagnosis, assessment of disease activity and severity, and evaluation of drug effects. In this context, biomarkers are ideals, due to their characteristics of non-invasive and nonexpansive measures. Concerning the diagnosis, no marker seems able to satisfy the needs to diagnose OA in pre-radiological stages and to identify different subsets of OA. Instead, biomarkers are useful in the assessment of disease activity and the prevision of its outcome. In the recent years, stimulated by the recent introduction of high sensitive immunoassays, number of studies have suggested a role of C-reactive protein (CRP) as marker of activity or severity of OA. Furthermore, higher CRP levels predict those patients whose disease will progress over 4 years. Since metalloproteases (MMPs) are highly involved in cartilage degradation, their levels or activities have been investigated to obtain information on OA severity or progression. Both in serum and synovial fluid (SF), the most abundant MMP is MMP-3. It has been proposed that pro-matrix MMP-3 may act as a marker for posttraumatic cartilage degradation. The molecular markers most useful in suggesting synthesis or degradation of cartilage originate from different articular sources such as cartilage, bone and synovial tissue. Serum hyaluronan (HA) is the most commonly used marker of synovial proliferation and hyperactivity, which may reflect the OA evolution. Other useful biochemical markers are serum keratin sulphate (KS), cartilage oligomeric matrix protein (COMP), YKL-40, and urinary C-terminal crosslinking telopeptides of collagen types I and II (uCTX-II). COMP concentration in SF from lavage as well as in serum is an early indicator ofradiographic progression at follow up. Furthermore, COMP was the most sensitive test for identifying affected subjectswith the genetic form of premature OA. uCTX-II is well correlated with radiological severity of both knee and hip OA and, in addition, the combined measurements of uCTX-II and serum HA seem the best predictor of the structural progression of hip OA.