Hyaluronans are polysaccharide molecules that occur naturally in synovial fluid; they help to create a viscous environment, cushion joints, and maintain normal function. The American College of Rheumatology recommends intra-articular injection of hyaluronans, which are available as several distinct therapeutic products, as an alternative to oral analgesics or nonsteroidal anti-inflammatory drugs for the symptomatic treatment of pain associated with osteoarthritis of the knee. A large body of literature supports the clinical efficacy and safety of this therapeutic class for this indication, although there are differences between the marketed products and they should be evaluated independently. Preliminary work investigating the use of hyaluronans for osteoarthritis in joints other than the knee has also produced promising results. There is growing evidence that hyaluronans, the biology of which is complex, may also have structure-modifying activity. Thus, compared with currently approved nonoperative therapies for osteoarthritis, hyaluronans may also have beneficial effects on the disease process in osteoarthritis.