The long history of influenza drug development has both contributed practical advances in antiviral chemotherapy and improved the understanding of influenza pathogenesis and epidemiology. The role played by these antivirals continues to grow with the dual threats of seasonal and pandemic influenza. The neuraminidase inhibitors are proven effective for the chemoprophylaxis and treatment of influenza A and B, although early therapy is essential for disease mitigation. Studies of topically applied zanamivir have demonstrated the importance of viral replication in the lower respiratory tract, even in uncomplicated influenza. Antiviral resistance, especially to the M2 ion channel inhibitors, sometimes limits clinical utility. Oseltamivir-resistant variants may emerge during treatment but have not yet circulated widely and are usually less fit than wild-type virus; most retain susceptibility to zanamivir. The transmission fitness cost of these resistant variants is drug-, neuraminidase subtype-, and mutation-specific. Continued vigilance in drug resistance surveillance is imperative, as is research into the development of new agents that will provide the potential for alternative and combination antiviral therapy.