Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) has already been considered as an attractive molecular target for the treatment of human metabolic disorders. Pleiotropic functions beyond this limit, such as anti-inflammatory and anti-proliferative effects against several pathological states, including atherosclerosis, osteoporosis and cancer, are currently being explored. Several natural and synthetic PPAR-gamma ligands have been the focus of extensive research effort as potent anti-inflammatory agents in diverse disease states. In the last decade, accumulative experimental evidence has further suggested that PPAR-gamma is involved in several inflammatory signaling pathways associated with arthritis. PPAR-gamma appears to be expressed by major cell populations in joints, such as chondrocytes, synoviocytes, fibroblasts and endothelial cells. PPAR-gamma ligands have also been shown to inhibit major inflammatory signaling pathways, reducing the synthesis of cartilage catabolic factors responsible for articular cartilage degradation in arthritis. In the present review the crucial role of PPAR-gamma ligands in arthritis and the underlying mechanisms participating in essential inflammatory signaling pathways are summarized. Taking into consideration the data so far, PPAR-gamma ligands seem to represent potential therapeutic agents in the aim to reduce mainly the inflammation implicated in arthritis. However, the precise molecular mechanisms through which PPAR-gamma ligands exert their actions are strongly recommended to be clarified, as both receptor-dependent and -independent actions were shown to be elicited.