Influenza A viruses of avian origin represent an emerging threat to human health as the progenitors of the next influenza pandemic. In recent years, highly pathogenic avian influenza H5N1 viruses have caused unprecedented epizootics on three continents and rare but highly fatal disease among humans exposed to diseased birds. Avian viruses of the H7 and H9 subtypes have also infected humans but generally resulted in far milder disease, yet they too should be considered as possible pandemic threats. Influenza virus infection elicits a complex network of host immune responses that, in uncomplicated influenza, results in effective control of the virus and the development of long-term memory responses. However, fatal avian H5N1 virus infection in both humans and experimental mammalian models is characterized by a high viral load in the respiratory tract, peripheral leukopenia and lymphopenia, a massive infiltration of macrophages into the lung, and dysregulation of cytokine and chemokine responses. This review focuses on avian influenza viruses as a pandemic threat, their induction of host innate immune responses in mammalian species, and the contribution of these responses to the disease process.