ABSTRACT Pathogenic bacteria, such as Yersinia pestis, are exposed to a wide range of environments within the host and have to be able to adapt to changes in the surrounding environment to establish an infection. One of the most peculiar features of the Y. pestis physiology and virulence is its stringent dependence on alkali/alkaline cations, primarily Ca2+. Despite the importance of calcium in the regulation of Y. pestis virulence factor production, virtually nothing is known about the mechanism of membrane transport of calcium in this organism. In Y. pestis, several different proteins potentially mediate the transport of Ca2+ across the bacterial membrane and some of these proteins are predicted to be able to integrate Ca2+, Na+, and pH homeostasis in this organism. Elucidation of the role of these transport systems in the physiology and ultimately pathogenicity of Y. pestis will allow the assessment of their potential as targets for the development of a novel class of antimicrobials with a completely new mechanism of action.