Osteoarthritis is associated with structural and functional changes in both the peripheral tissues and the central nervous system. A growing body of evidence demonstrates that pain severity in osteoarthritis is poorly correlated with radiographic disease severity, indicating that pain is driven and maintained by central nervous system mechanisms. This presentation will examine the evidence for the relationship between peripheral disease severity and pain, including the potential role of inflammation as a mediator of pain sensitization. Changes in the central nervous system, termed neural ‘plasticity’, manifest as a variety of mechanisms in osteoarthritis including increased activity in central pain pathways (‘central sensitization’) and reorganization of brain regions. These changes will be outlined, including the use of central sensitization measures to predict the development of chronic post-operative pain following total knee arthroplasty. Evidence for a range of new plasticity-based treatments including non-invasive brain stimulation, peripheral electrical stimulation and brain ‘priming’ with the potential to boost conservative management and post-surgical rehabilitation will be examined. Finally, early evidence for the presence of difference phenotypes in knee osteoarthritis based on unique combinations of biochemical markers, pain biomarkers, physical impairments, and psychological factors, that may provide the basis for mechanism-based diagnosis and individualized treatment in future, will be discussed.