The alkaline phosphatases comprise a heterogeneous group of enzymes that are widely distributed in mammalian cells. They often are associated with cell membranes, but their exact physiologic function is unknown. Despite this, alkaline phosphatase activity is a very useful serum biochemical indicator of liver disease, particularly cholestatic disease. However, increases in the activity of alkaline phosphatase in serum and other body fluids may reflect physiologic or pathologic changes beyond those of hepatic origin. For example, nonhepatic increases in serum alkaline phosphatase activity are found in young animals, in pregnant and lactating females, and in association with high fat diets. Bone disease, endocrine disease, neoplasia, and other disorders can result in increased alkaline phosphatase activity. In addition, alkaline phosphatase activity may be increased due to induction by certain drugs such as glucocorticoids and anticonvulsants. In this article, we will review the physiologic and pathologic factors influencing the activity of alkaline phosphatase in serum and other body fluids, with an emphasis on disorders beyond liver disease.