Continuing occurrences of human infections with avian influenza A (H5N1) viruses have ignited increasing fears that the next influenza pandemic is imminent. Fortunately, options for antiviral prophylaxis and treatment have been improved dramatically since the previous pandemics by the availability of neuraminidase inhibitors such as zanamivir and oseltamivir. However, although the prophylactic and therapeutic efficacy of these drugs is well established for uncomplicated seasonal human influenza, clinical effectiveness seems limited for human H5N1 infections despite in vitro susceptibility and efficacy in animal studies. Factors which might contribute to this apparently limited efficacy include suboptimal dosing or routes of administration, suboptimal timing of treatment and the inability of antiviral drugs to interfere with immunopathology, and the development of drug resistance. Efforts to optimize the use of neuraminidase inhibitor treatment in H5N1 disease are urgently needed and might eventually aid in the judicious use of stockpiled neuraminidase inhibitors in the event of a pandemic.