Mammalian models, most notably the mouse and ferret, have been instrumental in the assessment of avian influenza virus pathogenicity and transmissibility, and have been used widely to characterize the molecular determinants that confer H5N1 virulence in mammals. However, while H7 influenza viruses have typically been associated with conjunctivitis and/or mild respiratory disease in humans, severe disease and death is also possible, as underscored by the recent emergence of H7N9 viruses in China. Despite the public health need to understand the pandemic potential of this virus subtype, H7 virus pathogenesis and transmission has not been as extensively studied. In this review, we discuss the heterogeneity of H7 subtype viruses isolated from humans, and the characterization of mammalian models to study the virulence of H7 subtype viruses associated with human infection, including viruses of both high and low pathogenicity and following multiple inoculation routes. The use of the ferret transmission model to assess the influence of receptor binding preference among contemporary H7 influenza viruses is described. These models have enabled the study of preventative and therapeutic agents, including vaccines and antivirals, to reduce disease burden, and have permitted a greater appreciation that not all highly pathogenic influenza viruses are created equal.