Osteoarthritis (OA) is among the most prevalent chronic human health disorders and the most common form of arthritis. It is a leading cause of disability in developed countries. This disease is characterized by cartilage deterioration, synovitis, and remodeling of the subchondral bone. There is not yet a satisfactory treatment to stop or arrest this disease process. Although several candidates for therapeutic approaches have been put forward, recent studies suggest that activation of the transcription factor peroxisome proliferator-activated receptor gamma (PPARγ) is an interesting target for this disease. PPARγ is a ligand-activated transcription factor and member of the nuclear receptor superfamily. Agonists of PPARγ inhibit inflammation and reduce synthesis of cartilage degradation products both in vitro and in vivo, and reduce the development/progression of cartilage lesions in OA animal models. This review will highlight the recent experimental studies on the presence of PPARγ in articular tissues and its effect on inflammatory and catabolic responses in chondrocytes and synovial fibroblasts, as well as the protective effects of PPARγ ligands in arthritis experimental models. Finally, the role of PPARγ polymorphism in the pathogenesis of OA and related musculoskeletal diseases will also be discussed.