Extracellular matrix calcification with calcium pyrophosphate dihydrate (CPPD) and/or hydroxyapatite crystals commonly develops in osteoarthritic (OA) cartilage. Primary forms of articular cartilage CPPD crystal deposition and less commonly hydroxyapatite deposition can present as degenerative joint disease. Moreover, CPPD and hydroxyapatite crystals can traffic from cartilage to synovium and induce cytotoxic, catabolic, and inflammatory responses of chondrocytes and synovial lining cells, and promote synovial proliferation. Such changes have the potential to not only contribute to low-grade synovitis and inflammatory symptoms in OA but also to accelerate the progression of OA. In addition, CPPD and hydroxyapatite crystals are commonly found in joints with advanced OA. However, it is not clear that CPPD and hydroxyapatite crystal deposition actually worsen the course of primary OA. Instead, it appears that CPPD and hydroxyapatite crystal deposition in OA articular cartilage reflect aging, inflammation, altered IGF-I and TGFβ responsiveness, chondrocyte hypertrophic differentiation, changes in the closely linked metabolism of ATP, PP_i, and P_i, and possibly local changes in PTHrP expression and systemic changes in PTH. As such, OA pathogenesis richly informs us on mechanisms that drive articular cartilage calcification. Conversely, the presence of cartilage calcification informs us about pathogenesis and progression factors in subsets of affected subjects with OA.