The liver contains two systems for the removal of ammonia—the urea cycle and the enzyme glutamine synthetase. These systems are expressed in a complementary fashion in two distinct populations of hepatocytes, referred to as periportal and perivenous cells. One of the unresolved problems in hepatology has been to elucidate the molecular mechanisms responsible for induction and maintenance of the cellular heterogeneity for ammonia detoxification. There is now a potential molecular explanation for the zonation of the urea cycle and glutamine synthetase based on the Wnt/β-catenin pathway. BioEssays 28: 1072–1077, 2006. © 2006 Wiley Periodicals, Inc.