The pathogenesis of osteoarthritis (OA) appears to be the result of a complex interplay between mechanical, cellular and biochemical forces. Obesity is the strongest risk factor for disease onset in the knee, and mechanical factors dominate the risk for disease progression. OA is a highly prevalent and disabling disease. The current pre-eminent focus in OA research and clinical practice is on persons with established radiographic symptomatic disease. This is the very end-stage of disease genesis, and modern therapies hence are largely palliative. In an effort to mitigate the rising tide of increasing OA prevalence and disease impact, we need to focus more on preventing the onset of disease and modifying the structural progression of OA. Greater therapeutic attention to the important role of mechanical factors, joint injury and obesity in OA etiopathogenesis, is required if we are to find ways of reducing the public health impact of this condition.