The COVID-19 pandemic has generated many urgent questions on the origin, trajectory, and host preference of its causative betacoronavirus SARS-CoV-2, as well as renewed focus on other potentially zoonotic viruses. Several species of birds and wild bats can serve as reservoirs and/or mechanical vectors for many infectious viruses including influenza-A, SARS-CoV, MERS, and Ebola. Although substantial progress has been made, there are still major gaps in understanding the emergence, transmission, and adaptation of zoonotic avian- and bat-borne viruses. A major challenge is the dearth of suitable infection and immunity models. Extrapolating data from infection studies in human cell lines or rodents is limiting, as evolutionarily optimized immune factors function differently in non-hosts.