Neonatal liver insufficiency is a rare, but unfortunately often deadly disease. It is defined as a functional liver failure that occurs within the first 28 days of life. Gestational alloimune liver disease, metabolic diseases, viral infections and shock are considered to be the most significant causes of neonatal liver failure. Clinical presentation is often unspecific and, unlike in the case of adults, it rarely includes encephalopathy which is again especially difficult to recognize in newborns. The most important clinical features are coagulopathy and hypoalbuminemia, reflecting the failure of synthetic liver function. The diagnosis of neonatal liver insufficiency is a challenge and requires a multidisciplinary approach, while early recognition of liver failure and detection of the underlying cause is of great importance since it dictates further diagnostic and therapeutic treatment and affects the outcome. Therefore, neonatal liver insufficiency should be considered in every ill newborn without a clear cause of disease and in every newborn with signs of liver disease, with prompt referral to a specialized pediatric center.