Three broad factors, occurring concurrently, prevent elimination of highly pathogenic avian influenza caused by viruses of the H5N1 subtype (H5N1 HPAI) in countries and subregions where infection has remained endemic. These factors are the nature of the poultry sector, the quality of veterinary and animal production services (both public and private) serving the poultry industry, and the extent and level of commitment at all levels to virus elimination. Most of these countries have developed and adopted programs for progressive control of H5N1 HPAI, focused on the local factors hindering elimination of the viruses. Based on the rate of implementation of these measures over the last 5 to 7 yr (during which time there has been unprecedented financial and technical support from the international donor community), it is not expected that global eradication of H5N1 HPAI viruses can be achieved within the next 10 yr. If the “classical” approach to control, based around early case detection and culling, were adopted in a zone containing millions of free-running ducks, the work load required to complete even the first round of testing would exceed existing capacity. There would be no guarantees of sustained success locally, especially if the viruses are not eradicated regionally.