Osteoarthritis (OA) is a disease of the whole joint, with the most distinct changes occurring in the cartilage and underlying subchondral bone (the “osteochondral unit”). The osteochondral unit functions to maintain cellular and mechanical homeostasis of the joint. Bone marrow lesions (BMLs) are magnetic resonance imaging (MRI) pathology of subchondral bone commonly seen in individuals with early OA (pre-symptomatic, pre-radiographic) and established OA. Longitudinal studies have demonstrated a strong association between BMLs and severity of symptoms (pain) and structural progression (cartilage loss). BMLs are emerging as useful diagnostic and prognostic markers in OA, and potentially represent a therapeutic target for this disease, but what these MRI signals represent at the local tissue level, and how they develop in OA, remains poorly understood. We have recently undertaken a comprehensive characterisation of BMLs at the tissue level in human OA tibiae (1). A multi-modal tissue level analysis of the entire osteochondral unit associated with BMLs (inclusive of non-calcified and calcified cartilage, subchondral bone plate and trabeculae, and bone marrow) revealed that the presence of a BML is indicative of more advanced cartilage and subchondral bone degeneration. Specifically, a BML is associated with reduced cartilage volume, tidemark duplication, increased density of vasculature penetrating into the cartilage, and higher OARSI scores. BML subchondral bone changes include thicker bone plate, increased trabecular bone volume and plate-like structure, increased osteoid volume and thickness, and a striking increase in accumulated bone microdamage. In addition to the cartilage and bone changes, BML bone marrow is distinguished by an increased presence of oedema, fibrosis, necrosis, fibrovascular cyst-like formations, and increased vascular density. This presentation will discuss these novel osteochondral data for BMLs in human knee OA, particularly the potential role for MRI-sequence specific BMLs as biomarkers of OA disease severity, and explore the mechanical and metabolic origins for BML development.