Development of multispecies well-differentiated airway epithelial cell (WD-AEC) models derived from either primary cells or airway organoids has led to novel options for in vitro characterization of host–pathogen interactions for viruses associated with the respiratory disease complex in livestock. Whereas assessment of adaptive immune responses to infection or vaccination currently still requires studies in animals, viral host restriction, tropism, entry, replication, virulence, and innate host responses of the respiratory epithelium can effectively be studied in WD-AEC cultures. Moreover, these models are also suitable for highly sensitive isolation of field strains of respiratory viruses that can replicate to relatively high titers without relying on multiple passages to generate adequate virus stocks with reduced risk of cell-culture adaptations compared to passaging in immortalized cell lines. In this review, we provide a brief overview of currently available methods and potential model applications.