Glycolysis is the metabolic sequence that converts glucose to pyruvate and lactate (ethanol and CO2 in yeast) and provides energy under both aerobic and anaerobic conditions. In the liver and other lipogenic tissues, pyruvate formed by glycolysis is in great part used for the synthesis offatty acids (1). Gluconeogenesis is the reverse of glycolysis; it consumes energy and provides glucose to fasted animals, as well as glucose 6-phosphate to microorganisms grown in the absence of glucose. It is thus essential for survival, because all cells require glucose derivatives for the synthesis of glycolipids, glycoproteins and structural polysaccharides, which are normal constituents of their membranes. Furthermore, glucose is the main fuel of the brain and is also the only energy source for the mammalian erythrocytes and avian retina (1). Because a short period of hypoglycemia may cause irreversible damage to the brain, a major role of the liver is to maintain a constant level of glycemia. This function is ensured by glycogen synthesis and breakdown, which are controlled by various hormones and also by the concentration of glucose itself (2, 3). The glycogen stores of the liver are, however, exhausted after a few hours of fasting, and the supply of glucose relies then entirely on its biosynthesis from nonglucidic stores, essentially amino acids, but also lactate and glycerol. Under these conditions, glycolysis is arrested in the liver and greatly diminished in other tissues, since fatty acids and ketone bodies may serve as alternate fuels and allow for a glucose sparing effect. Another role of gluconeogenesis is the disposal of lactate produced by glycolyzing tissues, such as erythrocytes and muscle, particularly during intense exercise. Glycolysis and gluconeogenesis have most of their enzymes in common. These enzymes catalyze reversible reactions, the rate of which is controlled essentially by the concentration of substrates and products. Only at three levels are different enzymes used in glycolysis and gluconeogenesis, and they are the points of regulation discussed in this review. The activity of these enzymes is controlled in animals by several hormones and, in all organisms, by a series of metabolites; this control operates by various means, which include covalent modification of enzymes, formation of positive or negative effectors, and synthesis and degradation of protein. During the recent years, important progress has been made along these various lines; new substrates of cyclic AMP-dependent protein kinase have been discovered, but mechanisms not involving cyclic AMP have also been intensively investigated. Another discovery has been that of fructose 2, 6-bisphosphate, a potent regulator of both phosphofructokinase and fructose 1, 6-bisphosphatase.