Ebola, Sudan, and Marburg viruses are members of the filovirus family and are associated with frequently lethal outcomes when they infect humans. There are no FDA approved vaccines or therapeutics for these viruses and viable virus may only be studied in maximum containment (BSL-4). Historically, most outbreaks have been small and sporadic making conventional clinical trials impossible. As an alternative, the US FDA “Animal Rule” may be employed for these viruses, which relies on a well characterized animal model to provide efficacy data in the absence of human data. Our group has been characterizing and refining the models in parallel with testing the countermeasures. These studies have provided insights into infectivity, how these viruses adapt to new hosts, and how they persist in survivors.