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Osteoarthritis (OA) is a painful and life-altering disease that severely limits the daily activities of millions of Americans, and it is one of the most common causes of disability in the world. With obesity on the rise and the world’s population living longer, the prevalence of OA is expected to increase dramatically in the coming decades, generating burdensome socioeconomic costs. This review summarizes current pharmaceutical, nonpharmaceutical, and prospective new treatments for OA, with primary focus on the dietary supplement avocado/soybean unsaponifiables (ASU). ASU modulates OA pathogenesis by inhibiting a number of molecules and pathways implicated in OA. Anticatabolic properties prevent cartilage degradation by inhibiting the release and activity of matrix metalloproteinases and increasing tissue inhibitors of these catabolic enzymes. ASU also inhibits fibrinolysis by stimulating the expression of plasminogen activator inhibitor. Anabolic properties promote cartilage repair by stimulating collagen and aggrecan synthesis via inhibition of inflammatory cytokines such as interleukin (IL)-1, IL-6, IL-8, tumor necrosis factor, ERK, and prostaglandin E2. Chondroprotective effects are mediated by correcting growth factor abnormalities, increasing TGF-β, and decreasing vascular endothelial growth factor (VEGF) in synovial fluid. ASU also inhibits cholesterol absorption and endogenous cholesterol biosynthesis, which mediate reactive oxygen species pathology in chondrocytes. At the clinical level, ASU reduces pain and stiffness while improving joint function, resulting in decreased dependence on analgesics.