The pediatric population experiences preventable hospitalizations and serves as a reservoir for influenza and its transmission to other children as well as adults. As a consequence, the Advisory Committee on Immunization Practices has recommended initiating influenza immunization of children as young as 6 months of age through 23 months of age and, recently, up to 5 years of age. However, immunization of older children has not yet become a priority of the US Public Health Service. As a consequence, the importance of antiviral agents, particularly neuraminidase (NA) inhibitors, cannot be overemphasized. From an epidemiological perspective, influenza resulted in higher childhood mortality than did Bordetella pertussis infection in 2003-2004. During that season, 153 children died of influenza, and two-thirds were <5 years of age. Importantly, nearly 50% of these children were previously healthy, with no underlying illness. Currently, 2 NA inhibitors are approved for the treatment of influenza in children. Zanamivir is approved for children >7 years of age, and oseltamivir is approved for children >1 year of age. Arguably, the younger children are at particular risk for influenza complications and hospitalization. In placebo-controlled studies in children >1 year of age, oseltamivir therapy accelerated resolution of clinical illness and defervescence and decreased both the incidence of otitis media and the concomitant use of antibiotics. However, oseltamivir is not currently approved for children <1 year of age. Three clinical toxicology studies identified neurotoxicity in newborn rats administered this medication. In these preclinical toxicology studies, the dose of oseltamivir exceeded that which would be used in humans. In addition, the metabolism of oseltamivir is different in rats than in humans. A key component of influenza therapy is the possibility for development of resistance. Although in studies performed in North America, resistance was not a frequent event, it has been documented in Japanese children treated with this medication; the adequacy of the dose used has been questioned. Children represent only one unique study population among others. Individuals who are at increased risk for influenza infection include the elderly, the immunocompromised, and pregnant women. Collectively, antiviral medications must be evaluated in populations in which they have not yet been assessed. The development of additional antiviral drugs is an important recommendation for the future, so that antiviral resistance can be circumvented. Similarly, availability of drugs for children <1 year of age is mandatory. © 2006 by the Infectious Diseases Society of America. All rights reserved.