The cause of osteoarthritis (OA), the most common form of arthritis, is most likely multifactorial. No drug exists to slow the progression or reverse OA disease progression. Ample data support a key role of calcium-containing crystals, such as hydroxyapatite, in OA pathogenesis. The presence of these crystals, far higher in OA than in any other form of arthritis, correlates with the degree of radiographic degeneration. Calcium-containing crystals have potent biologic effects in vitro that emphasize their pathogenic potential. OA-associated matrix and chondrocyte alterations play an intimate role in the crystal deposition process. A major difficulty has been the lack of a simple technique for crystal identification in affected joints. Enhanced effort is needed to establish calcium-containing crystals as a therapeutic target in OA, as current data suggest an intimate association in its pathogenesis and progression.