Avian influenza viruses are major contributors to viral disease in poultry as well as humans. Outbreaks of high-pathogenicity avian influenza viruses cause high mortality in poultry, resulting in significant economic losses. The potential of avian influenza viruses to reassort with human strains resulted in global pandemics in 1957 and 1968, while the introduction of an entirely avian virus into humans claimed several lives in Hong Kong in 1997. Despite considerable research, the mechanisms that determine the pathogenic potential of a virus or its ability to cross the species barrier are poorly understood. Reverse genetics methods, i.e., methods that allow the generation of an influenza virus entirely from cloned cDNAs, have provided us with one means to address these issues. In addition, reverse genetics is an excellent tool for vaccine production and development. This technology should increase our preparedness for future influenza virus outbreaks.