The urea cycle was first described in 1932 by Krebs and Henseleit [1] (Figure 36.1). The urea cycle disorders (UCD) result from defects in the metabolism of the extra nitrogen produced by the breakdown of protein and other nitrogen-containing molecules. The incidence of these disorders in the United States is estimated to be at least 1 in 25,000 births, but partial defects may make this number much higher. In a comprehensive Japanese study covering several years the incidence was 1 in 46,000. Severe deficiency or total absence of activity of any of the first four enzymes (CPSI, OTC, ASS, and ASL) in the urea cycle or the cofactor producer (NAGS) results in the accumulation of ammonia and other precursor metabolites during the first few days of life. In milder (or partial) urea cycle enzyme deficiencies, ammonia accumulation may be triggered by illness or stress at almost any time of life, resulting in multiple mild elevations of plasma ammonia concentration. The hyperammonemia is less severe and the symptoms more subtle. The mainstays of treatment are (1) reducing plasma ammonia concentration, (2) pharmacologic management to allow alternative pathway excretion of excess nitrogen, (3) reducing the amount of nitrogen in the diet, (4) reducing catabolism through the introduction of calories supplied by carbohydrates and fat, and (5) taking measures to reduce the risk of neurologic damage. Defects in the fifth enzyme in the pathway, arginase, result in a more subtle disease involving neurologic symptoms.