Following the anthrax attacks of 2001 and the recent SARS outbreak, concerns about emerging and re-emerging infectious diseases have catalyzed a renewed interest in developing new vaccination strategies that provide rapid and flexible response options to future threats. Because the probability of encountering one of these exotic agents is unknown, it is essential that new vaccine formulations employ methods that provide effective protection and extremely good safety profiles if they are to be used by either military or civilian populations. One approach, which potentially satisfies these criteria, is the use of live recombinant Gram-positive commensal bacteria as expression vectors. This review provides an overview of the system, its advantages and limitations, and details an example of how Gram-positive commensal bacteria are being developed as a fifth generation vaccine against a Class A biowarfare pathogen, namely smallpox.