Hypophosphatasia is the rare, heritable form of rickets or osteomalacia that features low serum alkaline phosphatase (ALP) activity (hypophosphatasemia). Hypophosphatasemia in HPP is explained by a generalized reduction of activity of the "tissue-non-specific" isoenzyme of ALP (TNSALP) caused by loss-of-function mutation(s) within the TNSALP gene. The tissue-specific ALP isoenzyme genes are intact. In HPP, extracellular accumulation of the TNSALP substrate inorganic pyrophosphate (PPi), an inhibitor of mineralization, explains the skeletal disease. Characterization of this inborn error-of-metabolism verified a role for ALP in bone formation. The discoveries of elevated endogenous levels of three phospho compounds in HPP clarified the metabolic basis for this inborn-error-of-metabolism and the physiological role of TNSALP. HPP occurs worldwide. It is especially prevalent for inbred Mennonite families in Manitoba, Canada, where approximately 1 in 2500 newborns manifests severe disease, and approximately 1 in 25 individuals is a carrier. The prognosis for the various forms of HPP typically reflects the severity of the skeletal disease that corresponds with the age at presentation.