Leucine's wide-ranging metabolic influences have made it subject to special interest. It is abundant in the diet, especially in some milk and cereal proteins, in part due to its allocation of 6 codons in the genetic code, and individual dietary intakes range up to >250 mg · kg(-1) · d(-1). It influences many cell functions by various mechanisms, which include allosteric activation of enzymes, enabling ATP generation and insulin secretion from the pancreatic islet cell, and activation of signaling pathways. It is a mediator of the anabolic drive of dietary amino acids, stimulating anabolic hormone secretion and directly signaling protein deposition and growth through the stimulation of protein synthesis and restraint of proteolysis. Its signaling may involve the mammalian target of rapamycin complex and rapamycin-insensitive pathways responding to a leucine "transceptor," which combines leucine cellular transport, fueled by the intracellular-extracellular glutamine gradient, and a signaling response to changes in ionic and water balance and cell volume. In animal studies, dietary leucine supplementation has reversed many of the adverse influences of a high-fat diet, consistent with a benefit for healthy weight maintenance in humans for which evidence is accumulating. The implications for safety of leucine-supplemented diets are discussed in terms of adversely lowering valine and isoleucine concentrations and inducing hyperammonemia through overloading peripheral glutamine synthetic pathways. Finally, the apparently high human leucine requirement is explained in terms of both an adaptive metabolic demand model of requirements and the design and analysis of human studies, which may overestimate values.