The narrow host range of infection and lack of suitable tissue culture systems for the propagation of hepatitis B and C viruses are limitations that have prevented a more thorough understanding of persistent infection and the pathogenesis of chronic liver disease. With hepatitis B virus (HBV), this lack of knowledge 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. 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 chronic liver disease after adoptive transfer, and 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, and HCC in another. Although mice are not susceptible to HBV and HCV, their ability to replicate these viruses and to develop liver diseases characteristic of human infections provides new opportunities to study pathogenesis and develop novel therapeutics.