Infrequent infections of domestic animals and humans by Yersinia pestis, an endemic bacterial pathogen in many regions of the world, is a result of transmission by the bite of an infected flea and usually terminates with regional lymphadenitis (bubonic plague). However, progression to bacterial septicemia may result in lung colonization, organ failure and death in a high percentage of patients unless infection is controlled by early intervention with antibiotics. Due to the highly virulent nature of infections caused by inhalation of bacterial aerosols Y. pestis is listed by federal agencies as a Biodefense Category A pathogen. The protected intracellular bacterial growth of the earliest stage of infection suggest that cytolytic T cells (CTL) and innate immunity are critical to bacterial clearance. Several protein antigens recognized by CTL or antibodies are expressed by Y. pestis as components of the type III secretion system. Vaccine or therapeutic strategies targeting this virulence assembly may have the added benefit of providing cross-species protection.