For many years articular cartilage has been the focus of research aimed at improving understanding of and treatment for osteoarthritis. Although much is known about the tissue, research has had little success in elucidating the pathogenesis of generalised osteoarthritis. A new hypothesis is required. Substantial changes in many tissues, including bone, muscle, ligaments, and joint capsule, as well as cartilage, are increasingly recognised in this disease, and not all these changes are localised to the affected joints. There is also a well established link with obesity. These observations, the common origins of the mesenchymal cells that maintain these tissues, and the possible role of neuroendocrine factors that can regulate bone mass, result in the hypothesis that systemic factors that include altered lipid metabolism could explain the diversity of physiological changes in generalised osteoarthritis. If proven, this hypothesis could have important implications for a new approach to pharmacological intervention in the early stages of the disease.