Hepatocyte transplantation holds promise as an alternative to organ transplantation for the treatment of liver disease. Clinical trials of hepatocyte transplantation have demonstrated the long-term safety of the procedure, but only partial and short-term correction of metabolic disorders has been achieved. In the laboratory, host conditioning with low-dose liver-directed radiation facilitates repopulation of the native liver by transplanted hepatocytes and can lead to complete correction of models of hereditary metabolic deficiencies. Since the ability to diagnose and treat cell transplant rejection is limited, monitoring of peripheral blood donor specific CD154+ T cell activity for rejection risk following hepatocyte transplantation may allow optimization of immune suppression to produce better long-term disease correction. With respect to the most common indication for liver transplantation, decompensated end-stage cirrhosis, we have discovered that chronic injury stably reprograms the critical balance of transcription factors and that diseased cells can be returned to normal function by re-expressing a subset of critical transcription factors, a process similar to the type of reprogramming that induces somatic cells to become pluripotent or to change their cell lineage. Forced re-expression of HNF4α re-induces expression of the other hepatocyte-expressed transcription factors, immediately restores the phenotype of diseased hepatocytes in vitro, and rapidly reverses terminal liver failure in vivo by phenotypically correcting diseased hepatoctyes, not by stimulating their replacement by new hepatocytes or stem cells.