Viral respiratory tract infections are common in both children and adults. Mouse models of viral infection enable the characterization of host immune factors that protect against or promote virus infection; thus, mouse models are essential for interrogation of potential therapeutic targets. Moreover, they serve as critical models for the development of novel vaccine strategies. In this chapter, we describe methods for establishing mouse models of respiratory syncytial virus (RSV) and H1N1 influenza A virus infection. Protocols are provided for viral culture and expansion, plaque-forming assays for viral quantification, and infection of mice. Alternate modifications to the models are also described, and their potential impact is discussed.