Rhinovirus (RV) is the most prevalent etiologic agent of the common cold, and infections by RV species C (RV-C) are often associated with more severe illness, and have been strongly correlated with childhood development of asthma. Due to lack of in vitro and in vivo model systems capable of supporting the RV-C life cycle, few details of RV-C biology are understood about this recently discovered, clinically-relevant respiratory pathogen. To reveal the nature of virus-host interactions and study viral pathogenesis, the application of physiologically-relevant model systems that capture relevant cell types, differentiation states, and microenvironmental cues is essential. Applying these principles to our investigations of RV-C, I engineered in vitro and in vivo model systems to better understand the requirement of specific host factors for RV-C replication in human and mouse cells. Specifically, I utilized a pseudostratified in vitro model of human airway epithelium (HAE) to study RV-C replication, and applied CRISPR/Cas9 technology in these cultures to assess the specific role for stimulator of interferon genes (STING) in promoting viral replication. Since RV-C species tropism is highly restricted, I then applied our knowledge of RV-C replication in HAE cultures towards building an improved RV-C mouse model. Here, I first characterized RV-C replication in mouse lung cells in vitro, and demonstrated that human STING expression enhanced viral replication; second, I applied these findings in vivo, where I generated a transgenic mouse expressing the human ortholog of the RV-C receptor, cadherin-related family member 3 (CDHR3), along with human STING. While these mice lack overt symptoms typically associated with viral infection, they exhibited significantly increased viral replication 24 hours-post infection. Finally, to support ongoing efforts to further develop these mice as a robust small animal model of RV-C, I developed several novel cell lines which represent important tools to interrogate the impacts of other host factors on RV-C replication in mouse cells, which upon validation, can be re-engineered into these transgenic mice.