Hepatitis B virus (HBV) infections are a global health problem afflicting approximately 360 million patients. Of these individuals, 15-20 million are co-infected with hepatitis delta virus (HDV). Progress toward curative therapies has been impeded by the highly restricted host tropism of HBV, which is limited to productive infections in humans and chimpanzees. Here, we will discuss different approaches that have been taken to study HBV and HDV infections in vivo. The development of transgenic and humanized mice has lead to deeper insights into HBV pathogenesis. An improved understanding of the determinants governing HBV and HDV species tropism will aid in the construction of a small animal model with inheritable susceptible to HBV/HDV.