Osteoarthritis (OA) is a disease that predominantly, but not solely, affects the diarthrodial joints and results from an interaction between a number of complex mechanical and biological processes. Knowledge of the etiopathogenesis of OA has progressed significantly in the past few decades. A major characteristic of OA is articular cartilage destruction, yet it has become obvious that synovial inflammation, although not a primary cause of the disease, is among the significant structural changes that take place during its development. There is compelling evidence suggesting that secreted inflammatory mediators impact on the matrix homeostasis of articular tissue cells by altering their metabolism. Among these mediators that are responsible for the progression of the disease, evidence points to the proinflammatory cytokine interleukin-1 beta (IL-1ß) as the most important factor responsible for the catabolic process in OA. New members of the IL-1 super-family have recently been identified (ILF5-ILF10), some of which are suggested to be of interest for the arthritic diseases. Other proinflammatory cytokines, such as tumor necrosis factor (TNF)-α, IL-6, leukemia inhibitory factor (LIF), oncostatin M (OSM), IL-17, IL-18, and IL-8, are also considered potential contributing factors in the pathogenesis of OA. However, the exact role and importance of each in the OA process is not yet clearly established. In addition to cytokines, other inflammatory mediators also play a major role in the OA pathological process. These include nitric oxide (NO), eicosanoids (prostaglandins and leukotriene), and a newly identified cell membrane receptor family, the protease-activated receptors (PARs), in which an important role for PAR-2 in chronic arthritis has been suggested. All these topics will be discussed in this review and should help the reader to better understand the most recent advances concerning the inflammatory factors involved in the pathophysiology of OA.