Liver dysfunction is a common problem in the sick premature infant. The dysfunction is usually multifactorial and often underlies a combination of liver immaturity, comorbidities, and/or the presence of primary liver disease. The liver of the preterm infant has a paucity of bile ducts, low levels of many hepatic enzymes and transporters, and a small bile acid pool. Many other organ systems are immature as well and do not respond to stress the way they would later in infancy. This articles discusses how prematurity affects the liver, how it responds to secondary insults, and approaches to evaluation.