Osteoarthritis (OA) has been a frustrating disease for both the patient and the physician. Its current impact on society is tremendous and rivals that of ischemic heart disease in many regards. As the baby boomers reach late adulthood and the obesity epidemic rages on, OA will assume an even greater impact on society. The current OA armamentarium only reduces pain and perhaps improves function, but has no impact on the disease incidence or progression. Thus, the challenge for researchers to develop disease-modifying OA drugs becomes an issue of paramount importance. Several advances in the understanding of OA pathophysiology have provided a glimpse of optimism that disease modification is a real possibility.