The threat of bioterrorism worldwide has accelerated the demand for the development of therapies and vaccines against the Category B toxins: staphylococcal enterotoxin B (SEB), epsilon toxin (ETX) produced by Clostridium perfringens types B and D, and ricin, a natural product of the castor bean. The diverse and unique nature of these toxins poses a challenge to vaccinologists. While formalin-inactivated toxins can successfully induce antibody-mediated protection in animals, their usefulness in humans is limited because of potential safety concerns. For this reason, research is now aimed at developing recombinant, attenuated vaccines based on a detailed understanding of the molecular mechanisms by which these toxins function. Vaccine development is further complicated by the fact that as bioterrorism agents, SEB, ETX and ricin would most likely be disseminated as aerosols or in food/water supplies. Our understanding of the mechanisms by which these toxins cross mucosal surfaces, and importance of mucosal immunity in preventing toxin uptake is only rudimentary.