Osteoarthritis (OA) research is beginning to focus on developing structure (disease) modifying treatments that will stabilize or reverse morphological changes, thereby altering the underlying pathologic process. The ability of anti-arthritic agents to modify the course of disease has been investigated in a limited number of clinical trials. Agents studied in published clinical trials include glycosaminoglycan-peptide complex (GP-C), glycosaminoglycan polysulfate (GAGPS), diacerein, and glucosamine sulphate. These clinical trials have been difficult to interpret and compare because the patients studied are often inadequately characterized or are not comparable across studies. Studies also vary with respect to the outcome measures analyzed and the methodology applied to measurement and data analysis. Further, in general, the rate of radiographic progression of OA is slow and is not consistent across populations and patients with varying disease severity. In man, the radiograph has been the gold standard for evaluating treatments. Further longitudinal validation of the radiograph is needed. As techniques improve, variation in the system and the number of patients needed in studies are decreasing. It may be that the radiograph will not achieve the needed degree of validation and will be supplanted by magnetic resonance imaging as the surrogate marker of joint status.