Influenza continues to pose significant threats to global health. The disease remains life-threatening, especially in children, the elderly and immunocompromised patients. High mutation rate and genetic reassortment enhance antigenic diversity and generation of novel strains. These, and other related factors, have made influenza viruses more resistant to control strategies and have necessitated the need for development of novel and effective strategies for prevention and treatment of influenza. While vaccination is the preferred method for prevention of influenza virus infections, preparation of influenza vaccines has to be carried out annually, and this takes several months. Anti-influenza drugs would, therefore, be the most immediate resource for combating newly emerging influenza viruses, especially if available vaccines proved ineffective. This review discusses the prospects of using small interfering RNAs (siRNAs) for treatment of influenza. Challenges associated with anti-influenza RNA interference (RNAi) and future directions are also highlighted