Avian influenza, caused by highly pathogenic avian influenza viruses (HPAI) such as H5N1, is responsible for enormous economic losses in the poultry industry and poses a serious pandemic threat to public health. The overall aim of our study was to understand the genetic differences in the host that set the balance of disease resistance versus susceptibility for individual avian host-pathogen combinations. In order to examine the differences in the molecular signatures of hosts differing in their susceptibility to avian influenza we took a comparative transcriptomic approach. Six avian species - chickens/turkeys (highly susceptible with heavy mortality), geese/pigeons (tolerant carriers with only sporadic mortality) and ducks/crows (resistant to most AIV infections but having differential responses to virus of different H5 clades) were infected with two H5N1 strains from different clades, as well as lowly pathogenic H9N2 virus. Three tissues were analysed lung, ileum and brain. The knowledge gained from these comparisons can be used to develop sustainable strategies to control HPAI infections in domestic poultry.