Urea cycle disorders (UCD) are a group of rare inherited metabolic conditions of amino acid catabolism caused by an enzyme deficiency within the hepatic ammonia detoxification pathway. The presentation of these disorders ranges from life‐threatening intoxication in the neonate to asymptomatic status in adults. Late‐onset UCDs can present for the first time in adulthood and may mimic other causes of acute confusion or psychiatric diseases, and are often associated with neurological symptoms. Late‐onset UCDs may become apparent during periods of metabolic stress such as rapid weight loss, gastric bypass surgery, chronic starvation or the postpartum period. Early diagnosis is critical for effective treatment and to prevent long‐term complications of hyperammonemia. The challenges of management of adults include for example: (a) poor compliance to dietary and medical treatment which can result in recurrent hospital admissions; (b) severe neurological dysfunction; (c) the management of pregnancy and the postpartum period; and (d) access to multidisciplinary care peri‐operatively. In this review, we highlight a number of challenges in the diagnosis and management of adult patient with late‐onset UCDs and suggest a systematic management approach.