Osteoarthritis (OA) is an increasingly prevalent age-related joint disease with a high burden of personal and economic cost. The current failure to understand the underlying mechanisms of OA has prevented the development of effective disease modifying treatments. OA is a whole-joint disease, in which all components of the joint are affected, with particular involvement of the articular cartilage and subchondral bone. The disease is characterised by articular cartilage degeneration, with the addition of both generalised and focal changes of the subchondral bone. Bone marrow lesions (BMLs) are localised MRI features that are frequently found in the subchondral bone of patients with both early and late stage of OA. BMLs associate strongly with joint pain, structural degeneration of the articular cartilage, and predict progression to joint replacement. Our recent work in human knee OA has involved detailed histopathological examination of the osteochondral tissue that comprises BMLs. BML tissue is characterised by severe overlying cartilage degeneration and significant bone changes, which include increased trabecular bone volume with associated low bone matrix mineralisation, and increased microdamage (i.e. microcrack burden), vascularity and bone remodelling. Also, BML presence is shown to predict more extensive subchondral bone microstructural changes in the human OA knee. From this work, BMLs appear to represent a focal ‘hot zone’ of bone remodelling activity and may be the initiating epicentre of structural changes in the OA joint. The data support the use of BMLs as MRI image-based biomarkers to inform on the degenerative state within the OA knee. This presentation will review the role of subchondral bone focal changes in the initiation, development, and progression of OA, with an emphasis on BMLs in human OA and discussion of new data linking localised subchondral bone TGF-beta activity to impaired bone quality and the severity of human OA.