Morphological and Histochemical Description of Hepatocyte Heterogeneity. Studies on the functional heterogeneity of hepatocytes appeared in the literature as early as 1856 (1). In that publication, Beale described the heterogeneous distribution of “oil” among hepatocytes of the liver lobule as well as the different contribution of hepatocytes to bile secretion. In the 1920’9, Noel (2) proposed the division of the hepatic lobule into three functional zones. In the 1950’9, the work of Rappaport provided the concept that the simple liver acinus rather than the hepatic lobule represented the structural and functional unit of hepatic parenchyma (3). More recently, other groups have raised the possibility that the acinus, as described by Rappaport, may not fully describe the unit structure of the liver (4, 5). More data are needed to solve this discrepancy between Rappaport’s proposal and these studies. The essential feature of the acinar concept is that, within this unit, blood originating in terminal portal venules and hepatic arterioles perfuses hepatocytes unidirectionally. All hepatocytes of this unit are perfused with blood originating in the same vessels. Within the acinus, exchange of solutes between blood and hepatocytes occurs in a sequential manner, from hepatocytes located at the entry or “periportal” to those located at the exit or “perivenous” region. The splanchnic and arterial blood is progressively modified as it crosses the acinar sinusoids by uptake of substrates into and secretion from hepatocytes. It finally empties into hepatic venules reaching the systemic circulation. This sequential modification of sinusoidal blood implies that hepatocytes located at various points between the entry of blood into the acinus and the exit at the hepatic venules are perfused with blood of varying composition, creating a microenvironmental heterogeneity. In the 1960’s, the work of Novikoff (6), Shank, Morrison (7) and others (8), using histochemistry and measurements of enzyme activities in samples microdissected from periportal and perivenous areas, provided evidence for the heterogenous zonal distribution of various enzymes. Maximal differences were seen between hepatocytes located at the entry and exit of the acinus, and thus an arbitrary division of