Many Gram-positive spore-forming bacteria in the Firmicute phylum are important members of the human commensal microbiota, which, in rare cases, cause opportunistic infections. Other spore-formers, however, have evolved to become dedicated pathogens that can cause a striking variety of diseases. Despite variations in disease presentation, the etiologic agent is often the spore, with bacterially produced toxins playing a central role in the pathophysiology of infection. This review will focus on the specific diseases caused by spores of the Clostridia and Bacilli.