The significance of dietary arginine deficiency is often unrecognized since growth and nitrogen balance are generally positive. However, inadequate intakes of dietary arginine are typically associated with dramatic alterations in intermediary metabolism in mammals. Most of the symptoms that develop following arginine deprivation can largely be accounted for by a decreased efficiency of ammonia detoxification. However, species differences in the metabolic aberrations associated with arginine deficiency are clearly evident. Therefore, selected animals fed an arginine-deficient diet may serve as a useful model for the study of chronic hyperammonemia. In rats, mice, hamsters, guinea pigs and rabbits, the excretion of citric and orotic acid is a sensitive indicator of arginine availability. Increased orotic acid production is reduced or prevented by inclusion of the urea cycle intermediates arginine, citrulline or ornithine. However, growth in the rat is stimulated only when arginine or citrulline are included in the diet. Increased orotic biosynthesis is observed with increasing ammonia concentrations in rat, mouse and human liver and is reduced by in vitro arginine supplementation. The fatty infiltration of the rat fed an arginine-deficient diet is associated with changes in the ratio of purine to pyrimidine bases and is corrected by the dietary addition of adenine. The arginine-deficient rat should serve as a model for examining the dynamic interrelationship of the urea cycle with pyrimidine and purine biosynthesis.