Although most experts believe another influenza pandemic will occur, it is difficult to predict when or where it will appear or how severe it will be. Neither is there agreement about the subtype of the next pandemic influenza virus. However, the continuing spread of H5N1 highly pathogenic avian influenza A (HPAI) among poultry on several continents, associated with an increasing number of severe and fatal human infections, has raised the pandemic stakes.1 Genetically and antigenically divergent H5N1 HPAI strains appeared in 1997 and have been spreading globally since 2003.2-3 To date, epizootics in approximately 60 countries have caused a reported 291 human cases with 172 deaths.4 Although overshadowed by H5N1, at least 8 other poultry epizootics have recently occurred, some involving human infections and, uncommonly, human deaths.5 H5N1 epizootics are unique, however, in causing mortality in wild birds, occasional infections in mammals, severe human infections, and in rare instances possible human–to–human transmission.6 Do these unique features predict an impending H5N1 pandemic? Despite significant research, fundamental questions about how influenza A viruses switch hosts from wild birds and adapt to domesticated poultry, pigs or horses, and subsequently to humans, remain unanswered, especially those regarding the changes that allow human–to–human transmissibility.7 Given the potential for high morbidity and mortality, an approximation of the risk that H5N1 viruses will adapt to efficient human–to–human transmission would be extremely helpful for pandemic preparedness planning; despite the apparent inevitability of influenza pandemics, data accumulated over the past decade do not necessarily indicate pandemic emergence of H5N1.