Influenza is a threat that has been with humans throughout history, fueled by a constant race between host immunity and viral evolution. Control strategies rely on annual immunizations and require frequent updates of the vaccine, an expensive, cumbersome, and not always foolproof process. Efforts are therefore under way to develop vaccines that confer broadly cross-protective immunity to diverse influenza strains. Cross-immunity is pervasive in nature; in multistrain viral diseases such as influenza or dengue, response to a primary infection can profoundly influence response to the next strain encountered. Even unrelated viruses can be recognized by the same cross-reactive T cells. On page 722 of this issue , Gostic et al. show that severe infection with a bird flu virus depends on the individual's first encounter with influenza in childhood.