Hyperammonemia is usually defined as a plasmatic level above 80 µmol/L in infants up to 1 month of age and above 55 µmol/L in older children. Hyperammonemia is an acute life-threatening condition that can lead to severe neurologic impairment and cerebral edema.Acute hyperammonemia may induce a neurologic impairment leading to an acute life-threatening condition. Coma duration, ammonia peak level, and hyperammonemia duration are the main risk factors of hyperammonemia-related neurologic deficits and death. In children, hyperammonemia is mainly caused by severe liver failure and inborn errors of metabolism. In an acute setting, obtaining reliable plasma ammonia levels can be challenging because of the preanalytical difficulties that need to be addressed carefully. The management of hyperammonemia includes 1) identification of precipitating factors and cerebral edema presence, 2) a decrease in ammonia production by reducing protein intake and reversing catabolism, and 3) ammonia removal with pharmacologic treatment and, in the most severe cases, with extracorporeal therapies. In case of severe coma, transcranial Doppler ultrasound could be the method of choice to noninvasively monitor cerebral blood flow and titrate therapies.Hyperammonemia is usually defined as a plasmatic level above 80 µmol/L in infants up to 1 month of age and above 55 µmol/L in older children.1 Hyperammonemia is an acute life-threatening condition that can lead to severe neurologic impairment and cerebral edema. The most common causes of hyperammonemia in children are severe liver failure and inherited metabolic diseases. This article summarizes the pathophysiology, and the diagnostic and therapeutic management of hyperammonia in children, including medications, dialysis, and treatment novelties.