Abstract Understanding the effects of genetic diversity on human disease is the nexus of the Specialty Mouse Strains Resource (SMSR) grants. Recent findings that SARS-CoV-2 variants of concern (VOCs) can infect common laboratory mice creates both and opportunity and a concern. The concern is that SARS-CoV-2 has become a zoonotic agent that will impact research using mice. Little is known about how these VOCs will affect laboratory mice, whether mouse-to-mouse transmission is possible, or how to survey vivaria for infection. It is critical that we understand the course of infection, pathogenesis, and transmissibility including through germplasm so that strategies can be developed to protect research that depends on the use of mice. The data generated through this proposal will address these gaps in knowledge and will be of value to those developing policies and practices to prevent or manage outbreaks, protecting the research resources and infrastructure utilizing mice Paradoxically, the infection of VOCs in inbred mice also presents an opportunity. The differential infection among inbred strains for VOCs outlined in this proposal will increase our knowledge of host genetics of infection, providing a tremendous opportunity to improve our overall strategies in the design and use of mouse models for SARS-CoV-2, towards the ultimate goal of testing interventions and therapeutics.