Highly pathogenic H5N1 influenza viruses have become endemic in poultry populations throughout Southeast Asia and continue to infect humans with a greater than 50% case fatality rate. So far, human-to-human transmission of these viruses has been limited. Here, we discuss the molecular features of H5N1 influenza viruses that might affect their pathogenicity, and explain the current lack of efficient human-to-human transmission. Such knowledge is critical in evaluating the pandemic risk these viruses pose.