Bordetella species are respiratory pathogens that infect humans and other animals. A majority of the virulence factors expressed by these bacteria are regulated by a master control locus, BvgAS, a member of the two-component family of signal transduction systems. BvgAS senses environmental signals and mediates signal transduction by a phosphorylation cascade that leads to a biphasic transition between the Bvg+ and Bvg- phases. From natural host studies using Bordetella bronchiseptica, we have found that expression of Bvg+ phase factors, which include adhesins and toxins, is required for successful colonization of the mammalian respiratory tract. Suppression of the Bvg- phase motility phenotype is necessary for a successful interaction with the host. Although the Bvg- phase does not appear to be required in vivo, it does confer the ability to survive under conditions of severe nutrient deprivation. We hypothesize that the Bvg+ phase is necessary and sufficient for respiratory tract colonization and the Bvg- phase is adapted for survival in environments encountered during transmission between hosts.