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The Eastern woodchuck, Marmota monax , has been a useful model system for the study of the natural history of hepadnavirus infection and for the development and preclinical testing of antiviral therapies. The model has also been used for hepatitis delta virus (HDV). In this chapter several new applications of the woodchuck model of HDV infection are presented and discussed. The development of a woodchuck HDV inoculum derived from a molecular clone has facilitated the analysis of viral genetic changes occurring during acute and chronic infection. This analysis has provided insights into one of the more important aspects of the natural history of HDV infection—whether a superinfection becomes chronic. These results could renew interest in further vaccine development. An effective therapy for chronic HDV infection remains an important clinical goal for this agent, particularly because of the severity of the disease and the inability of current hepadnaviral therapies to ameliorate it. The recent application of the woodchuck model of chronic HDV infection to therapeutic development has yielded promising results which indicate that targeting the hepadnavirus surface protein may be a successful therapeutic strategy for HDV.