Osteoarthritis is a common disease, clinically manifested by joint pain, swelling and progressive loss of function. The severity of disease manifestations can vary but most of the patients only need intermittent symptom relief without major interventions. However, there is a group of patients that shows fast progression of the disease process leading to disability and ultimately joint replacement. Apart from symptom relief, no treatments have been identified that arrest or reverse the disease process. Therefore, there has been increasing attention devoted to the understanding of the mechanisms that are driving the disease process. Among these mechanisms, the biology of the cartilage-subchondral bone unit has been highlighted as key in osteoarthritis, and pathways that involve both cartilage and bone formation and turnover have become prime targets for modulation, and thus therapeutic intervention. Studies in developmental, genetic and joint disease models indicate that Wnt signaling is critically involved in these processes. Consequently, targeting Wnt signaling in a selective and tissue specific manner is an exciting opportunity for the development of disease modifying drugs for osteoarthritis.