The pathophysiology of osteoarthritis (OA) has been extensively studied. However, the basic approach to therapy, which consists of pain relief and maintenance of function, has not changed for decades. At present, there are no nonsurgical methods that clearly interfere with the natural history of OA or provide prolonged pain palliation. Much of OA disease progression is mediated by aberrant biomechanical forces or through pathologic responses to those forces. As understanding of these mechanisms improves, novel therapeutic approaches are being studied that may provide prolonged reductions in loading of OA joints. These new therapies may ultimately be shown to retard disease progression and palliate pain. This article reviews some of these strategies.