Increased blood ammonia (NH3) is an important causative factor in hepatic encephalopathy, and clinical treatment of hepatic encephalopathy is focused on lowering NH3. Ammonia is a central element in intraorgan nitrogen (N) transport, and modeling the factors that determine blood-NH3 concentration is complicated by the need to account for a variety of reactions carried out in multiple organs. This review presents a detailed quantitative analysis of the major factors determining blood-NH3 homeostasis – the N metabolism of urea, NH3, and amino acids by the liver, gastrointestinal system, muscle, kidney, and brain – with the ultimate goal of creating a model that allows for prediction of blood-NH3 concentration. Although enormous amounts of NH3 are produced during normal liver amino-acid metabolism, this NH3 is completely captured by the urea cycle and does not contribute to blood NH3. While some systemic NH3 derives from renal and muscle metabolism, the primary site of blood-NH3 production is the gastrointestinal tract, as evidenced by portal vein-NH3 concentrations that are about three times that of systemic blood. Three mechanisms, in order of quantitative importance, release NH3 in the gut: 1) hydrolysis of urea by bacterial urease, 2) bacterial protein deamination, and 3) intestinal mucosal glutamine metabolism. Although the colon is conventionally assumed to be the major site of gut-NH3 production, evidence is reviewed that indicates that the stomach (via Helicobacter pylori metabolism) and small intestine and may be of greater importance. In healthy subjects, most of this gut NH3 is removed by the liver before reaching the systemic circulation. Using a quantitative model, loss of this “first-pass metabolism” due to portal collateral circulation can account for the hyperammonemia observed in chronic liver disease, and there is usually no need to implicate hepatocyte malfunction. In contrast, in acute hepatic necrosis, hyperammonemia results from damaged hepatocytes. Although muscle-NH3 uptake is normally negligible, it can become important in severe hyperammonemia. The NH3-lowering actions of intestinal antibiotics (rifaximin) and lactulose are discussed in detail, with particular emphasis on the seeming lack of importance of the frequently emphasized acidifying action of lactulose in the colon.