The mouse is a common model used in evaluating drug metabolism and hepatitis infectivity. However, these models have limited value due to species difference in hepatic functions, leading to the creation of the chimeric mouse 12 years ago. These models were unique in that their hepatocytes had been replaced with human (hu) hepatocytes (dubbed the 'first-generation chimeric mouse'). Since then, the chimeric mouse has become a practical tool for this area of studies. However, some shortcomings have also been recognized. One major shortcoming is that the mouse cannot mimic hu-liver diseases due to immunodeficiency and also it is unable to provide sufficient amounts of blood for analysis compared to the rat. There are also issues around donor-to-donor variability of hu-hepatocytes such as variable engraftment efficiency.