Osteoarthritis of the knee is common, increasing with age in both women and men, but is generally more prevalent in women following the fourth decade. Osteoarthritis may be primary/idiopathic or secondary as a consequence of trauma, surgery, infection, or another disease process. Normal articular cartilage is composed of an extracellular matrix and chondrocytes. This matrix contains water, collagen fibers, and proteoglycan macromolecules cross-linked into an integrated network with hyaluronic acid. Osteoarthritis represents an imbalance in the destructive and synthetic processes of the cartilage that leads to erosion of the cartilage. In addition, there is a decreased concentration and viscosity of the synovial fluid in osteoarthritic patients, and this may decrease the lubricating and cushioning properties of the joint. There is also an underlying inflammation of the synovium, as well as damage or reactive changes in the subchondral bone. The entire process is thought to involve a complex interaction of cells and soluble mediators such as cytokines, growth factors, inflammatory mediators, metalloproteinases, and chondrodegradative enzymes. Understanding the biochemical and molecular changes that occur in the joint is requisite to the development of treatments for osteoarthritis of the knee that address both the symptoms of pain and loss of mobility as well as the underlying disease progression. The clinical goal of the management of osteoarthritis should be to treat not only the symptoms of the disease, such as pain and decreased mobility, but also the underlying pathology of the degenerative process.