Woodchuck hepatitis virus (WHV), a member of the Hepadnaviridae, is closely related to hepatitis B virus (HBV) in its virus structure, genetic organization, and mechanism of replication. As with HBV in man, persistent WHV infection is common in natural woodchuck populations and is associated with chronic hepatitis and hepatocellular carcinoma (HCC). In 1980, a program was initiated to develop the woodchuck as an experimental model of hepadnavirus infection and disease. The experimental studies have established that WHV causes HCC in woodchucks. Chronic WHV carriage as an outcome of experimental infection is a function of animal age at time of exposure, virus dose, and, possibly, virus strain. Almost all (97%) chronic carriers developed histologically confirmed HCC within 3 years; no HCC developed in uninfected animals held concurrently in the same laboratory setting. The model has application to studies of the underlying mechanisms of hepadnavirus-induced hepatocarcinogenesis and to the development of prophylactic and therapeutic strategies of disease control.