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Inorganic pyrophosphate (PP_i) regulates certain intracellular functions and extracellular crystal deposition. PP_i is produced, degraded, and transported by specialized mechanisms. Moreover, dysregulated cellular PP_iproduction, degradation, and transport all have been associated with disease, and PP_i appears to directly mediate specific disease manifestations. In addition, natural and synthetic analogs of PP_i are in use or currently under evaluation as prophylactic agents or therapies for disease. This review summarizes recent developments in the understanding of how PP_i is made and disposed of by cells and assesses the body of evidence for potentially significant physiological functions of intracellular PP_i in higher organisms. Major topics addressed are recent lines of molecular evidence that directly link decreased and increased extracellular PP_i levels with diseases in which connective tissue matrix calcification is disordered. To illustrate in depth the effects of disordered PP_i metabolism, this review weighs the roles in matrix calcification of the transmembrane protein ANK, which regulates intracellular to extracellular movement of PP_i, and the PP_i-generating phosphodiesterase nucleotide pyrophosphatase family isoenzyme plasma cell membrane glycoprotein-1 (PC-1).