The threat of highly virulent avian influenza, such as H5N1 and swine-origin H1N1 influenza viruses, bring out an urgent need to develop a universal influenza vaccine, which may provide cross-protection against different strain of influenza A viruses. The extra-domain of influenza M2 protein (M2e), which is almost completely conserved among all subtypes of influenza A viruses, is considered as a promising candidate target for the development of a broad-spectrum recombinant influenza A vaccine. The results of several preclinical studies with M2e protein, with or without carriers, have already proved the successful protection of M2e-based vaccinated animal model against lethal challenge of heterologous and homologous influenza A viruses. Recently, the results of Phase I/II clinical trail studies with M2e-based vaccines have raised hopes for considering these vaccines against seasonal and pandemic influenza A strains. Hence, it is expected that more and more effective and safe universal influenza vaccines based on M2e will be developed for prevention of seasonal and pandemic influenza in the near future.