The current vaccine for anthrax has been licensed since 1970 and was developed based on the outcome of human trials conducted in the 1950s. This vaccine, known as anthrax vaccine adsorbed (AVA), consists of a culture filtrate from an attenuated strain of Bacillus anthracis adsorbed to aluminum salts as an adjuvant. This vaccine is considered safe and effective, but is difficult to produce and is associated with complaints about reactogenicity among users of the vaccine. Much of the work in the past decade on generating a second generation vaccine is based on the observation that antibodies to protective antigen (PA) are crucial in the protection against exposure to virulent anthrax spores. Antibodies to PA are thought to prevent binding to its cellular receptor and subsequent binding of lethal factor (LF) and edema factor (EF), which are required events for the action of the two toxins: lethal toxin (LeTx) and edema toxin (EdTx). The bacterial capsule as well as the two toxins are virulence factors of B. anthracis. The levels of antibodies to PA must exceed a certain minimal threshold in order to induce and maintain protective immunity. Immunity can be generated by vaccination with purified PA, as well as spores and DNA plasmids that express PA. Although antibodies to PA address the toxemia component of anthrax disease, antibodies to additional virulence factors, including the capsule or somatic antigens in the spore, may be critical in development of complete, sterilizing immunity to anthrax exposure. The next generation anthrax vaccines will be derived from the thorough understanding of the interaction of virulence factors with human and animal hosts and the role the immune response plays in providing protective immunity.