Osteoarthritis is a progressive degenerative disease of the joints in which the articular cartilage within the joints deteriorates with associated juxta-articular bone formation. While the etiology of OA is still under investigation, preclinical studies have determined that the Wnt/β-catenin signaling and bone morphogenic signaling pathways are important for the formation and repair of the joint tissues, and the effects are on both the phenotype and function of the joint tissue cells. In addition, individuals with polymorphisms in the gene, FRZB, that codes for the wnt signaling protein secreted frizzled related protein 3 (sFRP3) have higher risk of developing OA. A number of proof-of-concept preclinical studies have been performed on inhibitors of the Wnt signaling pathway, and have altered the disease progression. Proof of concept studies assessing the regenerative capacity of mesenchymal stem cells as treatments for painful knee OA have reported both encouraging and discouraging results. Therefore, the identification of the molecular pathways that are responsible for joint formation and repair has led to the development of new novel interventions for the treatment of OA that are now entering clinical trials. The ability to slow or reverse the progression of osteoarthritis may soon be within our reach.