Key advances over the past three decades have allowed the evolution of hepatocyte transplantation from its use as an experimental tool to study liver cell biology to the initial application as a potential treatment modality for patients with liver disease. Although little is known about the cellular and molecular mechanisms regulating the fate of transplanted cells, studies in animal models of liver disease clearly suggest that transplanted hepatocytes have the potential to repopulate diseased livers and correct metabolic defects. Based on these experiments, human hepatocytes have been used in the treatment of children and adults with metabolic disease and liver failure. In initial trials, the improved clinical course following hepatocyte transplantation points to a potential role of the technique as an adjunct to liver transplantation.