Deficiency of any of the five enzymes in the urea cycle results in the accumulation of ammonia and leads to encephalopathy. Episodes of encephalopathy and associated systems are unpredictable and, if untreated, are lethal or produce devastating neurologic sequelae in long-term survivors. Although these disorders do not produce liver disease, the consequences of hyperammonemia resemble those seen in patients with hepatic failure or in a transient interference with the urea cycle, as seen in some forms of organic acidemias. Therefore, investigation for hyperammonemia in any infant or child with altered mental status (in the absence of obvious causes, such as trauma, infection or poisoning) is essential for prompt diagnosis of urea cycle disorders and institution of treatment to avoid brain damage and death. In this article, the function of the urea cycle and the diagnosis and management of the urea cycle disorders are addressed.