Bacillus anthracis is a Gram-positive, spore-forming bacterium representing the etiological cause of anthrax, a rare lethal disease of animals and humans. Development of anthrax countermeasures has gained increasing attention owing to the potential use of B. anthracis spores as a bioterror weapon. The various forms of infection by B. anthracis are characterized both by toxemia and septicemia, both of which are the result of spore entry into the host followed by their germination into rapidly multiplying, toxin-producing bacilli. Following the publication of the bacterial genome, proteomic studies were carried out to determine the protein composition of the spore and identify exposed vegetative (membrane-located or secreted) proteins. These studies included comparison of strains differing in their virulence, cultured under different conditions and, in some cases, were complemented by serological inspection, which addressed expression during infection of proteomically identified proteins and their immunogenicity. The proteomic approach emerged as a valuable strategy for the generation of a pool of potential B. anthracis protein targets for further evaluation in detection, diagnostics, therapy and prophylaxis, and contributed to the elucidation of some aspects of the pathogenesis of the disease.