Botulism is a severe neuroparalytic disease caused by toxins produced by several Clostridium species. Botulinum toxin has been of concern to the US military and its allies as a biowarfare weapon since World War II and, in more recent times, by the Centers for Disease Control and Prevention (CDC) as a potential bioterrorist threat to the public. The most effective means of defending against the toxin is by inducing a protective immune response through vaccination. Vaccination with an appropriate antigen will produce neutralizing antibodies that will bind to and clear toxin from the circulation before it can enter nerve cells and block neurotransmission. Immunity from botulism, however, has the disadvantage of precluding an individual from realizing the potential benefits of therapeutic botulinum toxin, if such a need were to arise. Botulinum toxin has been used in the treatment of numerous neuromuscular, autonomic, and sensory disorders since it was first approved for the management of strabismus and blepharospasm by the Food and Drug Administration (FDA) in 1989. Notwithstanding the value of the neurotoxin as a therapeutic drug, vaccines have been and will continue to be an important line of defense for those who work with the toxin (at-risk workers) and a select population of the military, law enforcement, and first responders. The first vaccine used to protect against botulinum neurotoxin was a chemically detoxified extract from Clostridium botulinum. A Pentavalent botulinum toxoid (PBT) vaccine in service today is administered under an Investigational New Drug (IND) application held by the CDC. Recombinant subunit vaccines are in development and a bivalent H(c) vaccine (rBV A/B (Pichia pastoris)) is presently being evaluated in a phase II clinical trial. This review focuses on botulism and the development of vaccines for its prevention.