Patients with life-threatening liver-based metabolic disorders require organ transplantation even though their metabolic diseases are typically the result of a single enzyme deficiency, and the liver otherwise functions normally. Hepatocyte transplantation holds great promise as an alternative to organ transplantation, and numerous studies in rodents indicate that transplants consisting of isolated liver cells can correct metabolic deficiencies of the liver. Consistent improvement in liver-based metabolic diseases has been reported in patients who have been treated by hepatocyte transplantation. Unfortunately, there have been no patients with complete correction of their metabolic enzyme deficiencies or evidence of long-term engraftment following hepatocyte transplantation. Based on extensive small and large animal studies, we have shown that conditioning part of the liver with low-dose focused radiation facilitates repopulation of the native liver by transplanted hepatocytes, can result in complete correction in models of hereditary metabolic deficiencies of the liver, and has led to the initiation of an FDA-approved clinical trial for the treatment of children and young adults with metabolic liver diseases. Unfortunately, the availability of human hepatocytes is limited as most cadaver donor livers are used for organ transplantation and the quality of human liver cells recovered from less-than ideal donors is often marginal. Patient-specific induced pluripotent stem (hiPS) cells have been created from a variety of somatic cell sources, and stem cell-derived hepatocytelike cells can be generated with many of the features of primary human hepatocytes. Their potential for use as source cells for transplantation has been enhanced by studies showing that such cells can be successfully used to model alpha-1-antitrypsin deficiency in vitro, and can be transplanted in Gunn rats (a model of Crigler-Najjar syndrome type 1) to correct hyperbilirubinemia and generate conjugated bilirubin species in the bile.