As resistance of influenza viruses to antiviral agents continues to evolve, new issues arise concerning appropriate therapy and novel therapeutic means that target influenza infections. Emergence of novel influenza mutations may lead to phenotypic as well as clinical resistance that may become a problem in serious influenza cases. Moreover, crucial public health issues emerge such as appropriate antiviral stockpiling for prepandemic and pandemic phases. The use of antiviral agents against seasonal, avian, and pandemic influenza should be an integral part of current pandemic preparedness planning and should be based on local and international surveillance data on antiviral resistance. As we tackle such resistance issues there appears to be an urgent need for developing strategies to conserve current antivirals against influenza, develop new agents or formulations that will exploit current pharmacokinetic knowledge, and study combination regimens.