Influenza A viruses are zoonotic pathogens that infect a variety of host species including wild aquatic birds, domestic poultry, and a limited number of mammals including humans. The error-prone nature of the virus's replication machinery and its ability to transmit among multiple hosts lead to generation of novel virus variants with altered pathogenicity and virulence. Spatial, molecular, and physiological barriers inhibit cross-species infections, particularly in the case of human infection with avian viruses. Pigs are proposed as a mixing vessel that facilitates movement of avian viruses from the wild bird reservoir into humans. However, the past decade has witnessed the emergence of highly pathogenic and virulent avian H5 and H7 viruses that have breached these barriers, bypassed the pig intermediate host, and infected humans with a high mortality rate, but have not established human-to-human transmissible lineages. Because influenza viruses pose a significant risk to both human and animal health, it is becoming increasingly important to attempt to predict their identities and pathogenic potential before their widespread emergence. Surveillance of the wild bird reservoir, molecular characterization and documentation of currently circulating viruses in humans and animals, and a comprehensive risk assessment analysis of individual isolates should remain a high priority. Such efforts are critical to the pursuit of prevention and control strategies, including vaccine development and assessment of antiviral susceptibility, that will have a direct impact on the well-being of humans and animals worldwide.