Summary: Ferrets have been demonstrated to be susceptible to laboratory infection of SARS-CoV-2, raising the possibility of natural transmission from humans into their pets in domestic settings. We demonstrate that ferrets may have host barriers that limit natural infection and transmission. First, we find no evidence of infection in 29 ferrets from a home with constant exposure to two adults with one confirmed and one suspected case of symptomatic COVID-19. Second, we analyze genetic sequences from viruses and hosts and demonstrate that ferrets have genetic factors that confer resistance to natural SARS-CoV-2 infection. These data suggest that ferret infection may require viral adaptation, and therefore ferrets may only be semipermissive models of SARS-CoV-2 disease or transmission. Alignment and phylogenetic data from genetic sequences have been deposited in a GitHub repository, [https://github.com/ksawatzki/Mustelid\_COVID\_PNAS][1] ([49][2]). All other data are included in the manuscript and/or supporting information. [1]: https://github.com/ksawatzki/Mustelid_COVID_PNAS [2]: #ref-49