ESLD affects millions of Americans, and HCV is a worldwide pandemic. Unfortunately, the ability to study liver disease and novel therapeutics experimentally in the laboratory is limited by an ongoing lack of small animal models. The development of rodents with livers chimeric for human hepatocytes may improve this situation. The authors' efforts currently use an immunodeficient or exogenously immunosuppressed animal with subsequent liver injury provided by chemical or surgical means. Cell transplantation with either human hepatocytes or human stem cells results in engraftment and subsequent "humanization" of an animal liver. Study of these animal models may lead to innovative approaches to the management of ESLD in both children and adults.