The narrow host range of infection supporting the long term propagation of hepatitis B and C viruses is a major limitation that has prevented a more through understanding of persistent infection and the pathogenesis of chronic liver disease (CLD). With hepatitis B virus (HBV), this has been partially overcome by the discovery and characterization of HBV-like viruses in wild animals. With hepatitis C virus (HCV), related Flaviviruses have been used as surrogate systems for such studies. Independent work has developed various mouse stains for the transplantation of human hepatocytes, which are then susceptible to infection with HBV and HCV. Other laboratories have developed transgenic mice that express virus gene products and/or support virus replication. Some HBV transgenic mouse models develop fulminant hepatitis, acute hepatitis, or CLD following adoptive transfer, while others spontaneously develop hepatocellular carcinoma (HCC), as in human infections. Among HCV transgenic mice, most develop no disease, but acute hepatitis has been observed in one model, while HCC appears in another. Other mouse models include the introduction of xenographs that replicate HBV or HCV. Although mice are not susceptible to these viruses, their ability to support virus replication and to develop liver diseases characteristic of human infections, provides new opportunities to study pathogenesis and develop novel therapeutics.