The chronically uremic rat has been used as a model to study amino acid metabolism in uremia. Uremic rats fed low protein diets (6% casein) survived longer than uremic rats receiving either higher levels of dietary protein or a low protein diet supplemented with a mixture of nonessential amino acids. Alterations in plasma amino acid levels were observed in the uremic rats and were similar to those found in patients with renal failure. Plasma concentrations of citrulline, free tryptophan, glycine and the methylhistidines were increased and levels of serine, ornithine, lysine, total tryptophan, tyrosine, and the tyrosine-phenylalanine ratio were reduced. The metabolic basis of the altered tyrosine-phenylalanine ratio in plasma was studied. Tyrosine aminotransferase (TAT) and phenylalanine hydroxylase (PHL) activity were normal in the liver, but renal PHL activity of was decreased as compared to control rats. Tissue concentrations of citrulline were also found to be raised in liver and muscle of uremic rats. The activity of ornithine transcarbamoylase, was reduced in the liver and arginine synthetase activity was decreased in the kidneys of uremic rats. Thus elevated citrulline levels in uremic tissue appear to be caused by a decrease conversion of citrulline to arginine in the kidney. Preliminary studies of tryptophan metabolism in uremic rats have shown elevated brain levels of 5-hydroxyindoleacetic acid and increased hepatic tryptophan oxygenase activity. Increased plasma amine levels were associated with altered activities of monoamine oxidase and diamine oxidase in kidney and other tissues.