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Neonatal liver failure (NLF) is a distinct and unusual clinical syndrome that requires a specialized approach to its management. This review establishes a definition of NLF and provides a literature-supported differential diagnosis. A specific approach to the diagnostic work-up of an infant with NLF based on this differential diagnosis is outlined. The role of mitochondrial-based diseases in the genesis of NLF is reviewed as well as current advances in the diagnosis and management of neonatal hemochromatosis. The unique range of diseases that cause NLF are associated with specific therapies, which are summarized.