It has been 40 years since the last influenza pandemic and it is generally considered that another could occur at any time. Recent introductions of influenza A viruses from avian sources into the human population have raised concerns that these viruses may be a source of a future pandemic strain. Therefore, there is a need to better understand the pathogenicity of avian influenza viruses for mammalian species so that we may be better able to predict the pandemic potential of such viruses and develop improved methods for their prevention and control. In this review, we describe the virulence of H5 and H7 avian influenza viruses in the mouse and ferret models. The use of these models is providing exciting new insights into the contribution of virus and host responses toward avian influenza viruses, virus tropism, and virus transmissibility. Identifying the role of individual viral gene products and mapping the molecular determinants that influence the severity of disease observed following avian influenza virus infection is dependent on the use of reliable animal models. As avian influenza viruses continue to cause human disease and death, animal pathogenesis studies identify avenues of investigation for novel preventative and therapeutic agents that could be effective in the event of a future pandemic.