Continued circulation of the highly pathogenic avian H5N1 influenza A virus has many people worried that an influenza pandemic is imminent. Compounding this is the realization that H5N1 vaccines based on current influenza vaccine technology (designed to generate protective antibody responses) may be suboptimal at providing protection. As a consequence, there is recent interest in vaccine strategies that elicit cellular immunity, particularly the cytotoxic T lymphocyte response, in an effort to provide protection against a potential pandemic. A major issue is the lack of information about the precise role that these 'hitmen' of the immune system have in protecting against both pandemic and seasonal influenza. We need to know more about how the induction and maintenance of cytotoxic T lymphocytes after influenza infection can impact protection from further infection. The challenge is then to use this information in the design of vaccines that will protect against pandemic influenza and will help optimize CD8(+) killer T-cell responses in other infections.