Spore germination is the first step in establishing Bacillus and Clostridium infections. Germination is triggered by the binding of small molecules by the resting spore. Subsequently, the activated spore secretes dipicolinic acid and calcium, the spore core is rehydrated and spore structures are degraded. Inhibition of any of the germination-related events will prevent development to the vegetative stage. Inhibition of spore germination has been studied intensively in the prevention of food spoilage. In this perspective, we propose that similar approaches could be used in the prophylactic control of Bacillus anthracis and Clostridium difficile infections. Inhibition of B. anthracis spore germination could protect military and first-line emergency personnel at high risk for anthrax exposure. Inhibition of C. difficile could prevent human C. difficile-associated disease during antibiotic treatment of immunocompromised patients.