Significant advances have occurred in the symptomatic management of osteoarthritis over the past several decades. However, the development of so called disease-modifying osteoarthritis drugs is in a more formative stage. Although increased knowledge of osteoarthritis pathophysiologic pathways provides more rational opportunity for targeting specific elements of the degenerative process, limitations in our ability to measure disease progression/regression hamper assessment. Development of more sophisticated plain radiographic techniques and the use of additional technologies such as magnetic resonance imaging and gadolinium-enhanced magnetic resonance imaging of cartilage provide potential for more reproducible approaches. Noninvasive biomarkers that reflect structural change are the subject of intense investigation. Studies describing disease-modification effects provide optimism that disease prevention, retardation, and reversal are attainable.