Osteoarthritis (OA) is a significant and growing concern to a large segment of the population. Effective treatments for slowing or stopping the progression of the disease are not available despite a great deal of investment-backed effort on the part of academia, government, and the pharmaceutical industry. Target selection has been problematic. Progress may also have been hindered to some extent by the prevalent cartilage-centric view of OA. Significant clinical development challenges remain for novel therapeutics in this area. This review elaborates on the challenges of disease-modifying OA drug development and points out specific therapeutic intervention strategies recently tried or currently being pursued.