Osteoarthritis is a major musculoskeletal cause of disability in the elderly, but current therapeutic approaches are insufficient to prevent initiation and progression of the disease. Genetic studies in humans have identified molecules involved in signalling cascades that are important for the pathology of the joint components. These include the bone morphogenetic protein (BMP) signalling, the wingless-type signalling and the thyroid pathway as well as apoptotic-related molecules. There is emerging evidence indicating that inflammatory molecules related to cytokine production, prostaglandin and arachidonic acid metabolism are also involved in susceptibility to osteoarthritis. All of these pathways are likely targets for pharmacological intervention. Genetic variation also affects pain due to osteoarthritis highlighting molecular mechanisms for pain relief. Moreover, combinations of genetic markers can be used to identify individuals at high risk of osteoarthritis and risk of total joint arthroplasty failure, which should facilitate the application of preventive and disease management strategies.