Universal and timely administration of a prepandemic vaccine is considered to be one of the most effective measures to reduce the incidence of pandemic influenza infection and consequently its morbidity and mortality. To provide the reader with basic insights into influenza virus infections, the threat of a pandemic and the challenges it poses for vaccine development. This review summarizes the reported preclinical and clinical data obtained with the prepandemic H5N1 vaccine adjuvanted with AS03. The AS03-adjuvanted prepandemic H5N1 influenza vaccine allows for antigen sparing, has a good safety and acceptable reactogenicity profile, induces an immune response that not only meets all European Committee for Medicinal Products (CHMP) and FDA requirements for the vaccine strain but also generates neutralizing antibodies that broadly cross-react against H5N1 drift strains, and finally conveys protection in a ferret model against lethal challenges with homologous and heterologous H5N1 viruses.