Creatine and phosphocreatine serve not only as an intracellular buffer for adenosine triphosphate, but also as an energy shuttle for the movement of high-energy phosphates from mitochondrial sites of production to cytoplasmic sites of utilization. The spontaneous loss of creatine and of phosphocreatine to creatinine requires that creatine be continuously replaced; this occurs by a combination of diet and endogenous synthesis. Vegetarians obtain almost no dietary creatine. Creatine synthesis makes major demands on the metabolism of glycine, arginine, and methionine. Large doses of creatine monohydrate are widely taken, particularly by athletes, as an ergogenic supplement; creatine supplements are also taken by patients suffering from gyrate atrophy, muscular dystrophy, and neurodegenerative diseases. Children with inborn errors of creatine synthesis or transport present with severe neurological symptoms and a profound depletion of brain creatine. It is evident that creatine plays a critical, though underappreciated, role in brain function.