The incidence of liver disease is increasing globally. The only curative therapy for severe end-stage liver disease, liver transplantation, is limited by the shortage of organ donors. In vitro models of liver physiology have been developed and new technologies and approaches are rapidly progressing. Stem cells might be used as a source of liver tissue for development of models, therapies, and tissue engineering applications. However, we have been unable to generate and maintain stable and mature adult liver cells ex vivo.