Factoring significantly into the global burden of influenza disease are high-risk populations that suffer the bulk of infections. Classically, the very young, very old, and pregnant women have been identified as high-risk populations; however, recent research has uncovered several other conditions that contribute to severe infection. By using varied animal models, researchers have identified molecular mechanisms underpinning the increased likelihood for infection due to obesity and malnourishment, as well as insight into the role sex hormones play in antiviral immunity in males, in females, and across the life span. Additionally, novel comorbidity models have helped elucidate the role of chronic infectious and genetic diseases in influenza virus pathogenesis. Animal models play a vital role in understanding the contribution of host factors to influenza severity and immunity. An in-depth understanding of these host factors represents an important step in reducing the burden of influenza among the growing number of people living with one or more chronic medical conditions.