Calcium pyrophosphate (CPP) crystal deposition (CPPD) is associated with ageing and osteoarthritis, and with uncommon disorders such as hyperparathyroidism, hypomagnesemia, hemochromatosis and hypophosphatasia. Elevated levels of synovial fluid pyrophosphate promote CPP crystal formation. This extracellular pyrophosphate originates either from the breakdown of nucleotide triphosphates by plasma-cell membrane glycoprotein 1 (PC-1) or from pyrophosphate transport by the transmembrane protein progressive ankylosis protein homolog (ANK). Although the etiology of apparent sporadic CPPD is not well-established, mutations in the ANK human gene (ANKH) have been shown to cause familial CPPD. In this Review, the key regulators of pyrophosphate metabolism and factors that lead to high extracellular pyrophosphate levels are described. Particular emphasis is placed on the mechanisms by which mutations in ANKH cause CPPD and the clinical phenotype of these mutations is discussed. Cartilage factors predisposing to CPPD and CPP-crystal-induced inflammation and current treatment options for the management of CPPD are also described.