Ruminant liver has a quantitatively unique array of substrates presented to it because of the extensive fermentation of dietary carbohydrate to organic acids in the gastrointestinal tract. The single largest input of dietary energy to the extrasplanchnic tissues is acetic acid derived from fermentation, which is largely unused by hepatic parenchyma. The other volatile fatty acids derived from fermentation, primarily propionate, are cleared extensively, but not completely, by the liver. This results in a marked concentration gradient for these acids across the liver lobule. L-lactate, derived from tissue metabolism, as well as variable amounts from rumen fermentation, is used by the liver at a rate lower than for propionate and below the predicted capacity based on in vitro enzymatic and intact cell capacity data. The net result of this selective utilization by the liver results in peripheral blood containing significant concentrations of L-lactate and acetate, but little of the other organic acids. Propionate carbon metabolized by liver cells is converted to glucose with little true loss of carbon, but the same is not true of lactate carbon. The energetic efficiencies by which propionate and lactate carbon are converted to glucose may be much less than optimal because of extensive cycling through pyruvate kinase, pyruvate carboxylase and phosphoenolpyruvate carboxykinase. Inhibition of this futile cycling may represent one avenue by which energetic costs of maintenance and production can be lowered in ruminants.