Thirteen hantavirus genotypes, associated with at least 12 sigmodontine reservoir rodents, have been recognized in the four countries that represent the Southern Cone of South America. Host–virus relationships are not as well defined as in North America; several Southern Cone hantaviruses appear to share a common host and some viruses do not occur throughout the range of their host. Although hantavirus–host relationships in the Southern Cone are less strictly concordant with the single-host–single-virus pattern reported elsewhere, recent studies suggest that much of the ambiguity may result from an incomplete understanding of host and hantavirus systematics. Although some Southern Cone host species are habitat generalists, some sympatric species are habitat specialists, helping to explain how some strict host–virus pairings may be maintained. In some cases, host population densities were higher in peridomestic habitats and prevalence of hantavirus infection was higher in host populations in peridomestic habitats. Seasonal and multiyear patterns in climate and human disturbance affect host population densities, prevalence of infection, and disease risk to humans. Unusually high hantavirus antibody prevalence in indigenous human populations may be associated with frequent and close contact with host rodents. Ongoing studies are improving our understanding of hantavirus–host ecology and providing tools that may predict human risk.