Influenza viruses continue to cause significant morbidity and mortality worldwide. With the threat of the emergence of a pandemic influenza strain, there is an urgency to develop new vaccine strategies that offer broad protection. The rational basis for the design of such vaccines comes from the use of animal models. Cotton rats are a helpful tool to study influenza disease pathogenesis and immunity because adaptation of human influenza strains is not required for virus replication in the lower respiratory tract and subsequent disease signs. This review describes innate and adaptive responses to influenza in infected cotton rats, and points out immune mechanisms that contribute to protection against disease.