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Gluconeogenesis occurs mainly in the liver, with a contribution from the renal cortex, and its reactions span the cytosol and mitochondria. Lactate, alanine, glycerol, and propionyl-CoA feed into the pathway at different points. Four irreversible bypass steps distinguish it from a simple reversal of glycolysis; the rate-limiting enzyme is fructose-1,6-bisphosphatase. Hormonal and metabolite signals regulate pathway activity, while mitochondrial export of oxaloacetate supports the sequence. The Cori and alanine cycles connect muscle and liver metabolism. Understanding these features provides a framework for considering fasting, ethanol-related inhibition, and the consequences of absent glucose-6-phosphatase.