Influenza is a seasonal disease that peaks every year in the winter months. Antigenic drift of the viral surface proteins, particularly the hemagglutinin (HA), is responsible for the virus's ability to evading the host's immune system, and for the severity of the disease. Pandemic influenza arises when an influenza virus carrying a novel HA gene enters into the naive human population, resulting in excess morbidity and mortality. Three major influenza pandemics were experienced in the last century and the emergence of a new pandemic strain is considered a matter of time. Our current understanding suggests that pandemic influenza strains arise from influenza viruses circulating in the natural reservoir, although the presence of intermediate hosts is considered essential in this process. Pigs and land-based birds have been shown to play a major role in the ecology of influenza viruses by providing an environment in which influenza viruses can change their phenotype, expand their host range, and eventually transmit to humans. In recent years, a great detail of attention has been placed on understanding the epidemiological and molecular factors that can lead to interspecies transmission of influenza viruses. In this review we will discuss the ecological and molecular aspects that lead to pandemic influenza as well as the intervention strategies at our disposal that can reduce the emergence of pandemic influenza strains and/or minimize their effects.