Anthrax continues to generate concern as an agent of bioterrorism and as a natural cause of sporadic disease outbreaks. Despite the use of appropriate antimicrobial agents and advanced supportive care, the mortality associated with the systemic disease remains high. This is primarily due to the pathogenic exotoxins produced by Bacillus anthracis as well as other virulence factors of the organism. For this reason, new therapeutic strategies that target events in the pathogenesis of anthrax and may potentially augment antimicrobials are being investigated. These include anti-toxin approaches, such as passive immune-based therapies; non-antimicrobial drugs with activity against anthrax toxin components; and agents that inhibit binding, processing, or assembly of toxins. Adjunct therapies that target spore germination or downstream events in anthrax intoxication are also under investigation. In combination, these modalities may enhance the management of systemic anthrax.