Serum levels of alkaline phosphatase (AP) have been used in the clinical evaluation of numerous diseases, including malignancies, for half a century. The aberrant expression of AP genes in cancer cells has led to the suggestion that APs are oncofetal proteins and thus, could be involved in tumorigenesis. Tumors which express these AP isozymes can be broadly divided into two groups: (a) those with an enhanced production of an isozyme normally expressed in the tissue (eutopic expression) and (b) those showing expression of one or more isozymes not identified in the normal tissue (ectopic expression). Moreover, many tumors show simultaneous expression of two or more different AP isozymes. In the absence of known biological functions of the AP isozymes several different mechanisms underlying their expression in tumor cells could explain the findings. In an attempt to clarify the function of APs, this laboratory is engaged in the study of unique properties of the mammalian APs as possible clues to their function, i.e., (a) the phosphatidylinositol glycan attachment of APs to the cytoplasmic membrane, (b) the uncompetitive inhibition properties of APs and (c) the extracellular matrix binding domain of APs. This laboratory is also undertaking the task of targeting each of the mouse AP isozymes by homologous recombination to generate mouse models of hypophosphatasia to analyze in detail the in vivo consequences of AP isozyme deficiencies.