OBJECTIVES: Osteoarthritis is a chronic disease characterized by irreversible damage to joint structures, including loss of articular cartilage, osteophyte formation, alterations in the subchondral bone and synovial inflammation. It has been shown that chondroitin sulfate interferes with the progression of structural changes in joint tissues and is used in the management of patients with osteoarthritis. METHODS: This review summarizes data from relevant reports describing the mechanisms of action of chondroitin sulfate that may explain the beneficial effects of the drug and examines the evidence for clinical efficacy of oral chondroitin sulfate in osteoarthritis. Data included in the review were derived from a literature search in PubMed. Literature searches were performed in PubMed using the search terms 'chondroitin sulfate', 'pharmaceutical-grade', 'osteoarthritis', 'randomized clinical trials', 'humans'. The MEDLINE database was searched from January 1996 through August 2012 for all randomized controlled trials, meta-analyses, systematic reviews, and review articles of chondroitin sulfate in osteoarthritis. RESULTS: Chondroitin sulfate exerts in vitro a beneficial effect on the metabolism of different cell lines: chondrocytes, synoviocytes and cells from subchondral bone, all involved in osteoarthritis. It increases type II collagen and proteoglycan synthesis in human articular chondrocytes and is able to reduce the production of some pro-inflammatory factors and proteases, to reduce the cellular death process, and improve the anabolic/catabolic balance of the extracellular cartilage matrix (ECM). Clinical trials have reported a beneficial effect of chondroitin sulfate on pain and function. The structure-modifying effects of chondroitin sulfate have been reported and analyzed in recent meta-analyses. The results in knee osteoarthritis demonstrate a small but significant reduction in the rate of decline in joint space width. Because chondroitin sulfate quality of several nutraceuticals has been found to be poor, it is recommended that pharmaceutical-grade chondroitin sulfate is used rather than food supplements in the treatment of OA. Chondroitin sulfate is recommended by several guidelines from international societies in the management of knee and hip OA. Furthermore, its safety profile is favorable when compared with many other therapies used in OA. CONCLUSION: Chondroitin sulfate is an effective and safe treatment option for patients with osteoarthritis.