One of two members of the family Filoviridae, the Ebola virus contains three subtypes that have been shown to cause disease in tangential hosts in sub-Saharan Africa: Ebola-Sudan, Ebola-Zaire, and Ebola-Côte d’Ivoire. Ebola hemorrhagic fever (EHF) is a very severe, often fatal, disease in humans and their closest biological relatives, the African apes. The first recognized human outbreak occurred in Zaire/Sudan in 1976 with the most recent epidemic occurring in Sudan in 2004. Experts have asserted that EHF threatens not only human populations but also the extirpation or extinction of apes in West Central Africa. The viral ecology and reservoir ecology of Ebola are still largely unknown, despite a decade of very intensive field investigations. Ebola experts—during a September 2004 session on EHF at a symposium entitled “One World, One Health” sponsored by the Wildlife Conservation Society and Rockefeller University—presented data on the epidemiology of EHF but were still unable to elucidate key aspects concerning the community ecology and anthropology of EHF outbreaks in Africa. The primary objectives of this paper are: (1) to present an historical overview of EHF as it relates to unanswered questions regarding the emergence, biogeography, human susceptibility, viral ecology/reservoir ecology, and cross-species transmission of the Ebola virus; and (2) to suggest that relevant insights regarding the maintenance and amplification hosts for the Ebola virus can be gleaned by integrating human disease ecology, human host genetics, the population dynamics of endangered African apes, and Afrotropical biogeography and human migration/ settlement patterns during the Pleistocene.