The hispid cotton rat (Sigmodon hispidus) has demonstrated excellent translational and predictive value in the study of respiratory syncytial virus (RSV). While the cotton rat model has many advantages over the mouse model, unfamiliarity with the species can serve as a deterrent to its use. Here, we review the most common protocols for studying RSV in the cotton rat model, including housing and handling, anesthesia and intranasal infection, drug administration, blood draws, and postmortem tissue collection. Using these basic protocols, investigators can pursue downstream applications similar to those available in other animal models, limited only by available species-specific or cross-reactive reagents.