THIS year marks the 70th anniversary of the discovery of alkaline phosphatase (ALP) (1). For the greater part of the past seven decades there has been universal appreciation by physicians of the important clinical insight that comes from measuring ALP activity in serum to detect and follow the course of hepatobiliary and skeletal disease (2). Since the 1930s, quantification of ALP activity has been a routine test in the hospital laboratory and it is likely the most frequently performed enzyme assay (1). Nevertheless, the physiological function of this protein that is ubiquitous in nature remains unclear (1, 3 5). As reviewed here, however, recent molecular studies of hypophosphatasia, a rare heritable form of rickets, have confirmed the long-held notion that ALP has a significant role in skeletal mineralization in humans. How ALP acts was clarified by the discoveries that several phosphocompound substrates for tissue-nonspecific ALP (TNSALP) accumulate endogenously in this inborn error of metabolism.