This review deals with factors that influence the virulence of influenza A virus. A high genetic and antigenic variability is demonstrated in a broad spectrum of influenza A viruses ranging from avirulent to lethal ones. Influenza A viruses have caused several epidemics and pandemics in the past and present that have cost millions of lives worldwide. Therefore these viruses still belong to the most important ones with strong impact on whole human population. Here, we discuss the latest findings concerning the role of individual viral proteins, interaction of the virus with the host immune system, and interspecies transmission and evolution of the virus. It is important to elucidate the genetic background of virulence of influenza A viruses, mechanisms involved in crossing the interspecies barrier, and mechanisms of destruction of the host cell by these viruses, and to identify the factors influencing the interaction between these viruses and the host immune defense system. This knowledge should help to estimate the threat of influenza A viruses with human pandemic potential to human population.